The Binding of Isaac: Rebirth: Most & Least Important Unlocks (Repentance+)

Steam Community guide by jnub.

What Even is This?

The Binding of Isaac: Rebirth is an amazing roguelite game with hundreds of unlocks to get. A lot of these unlocks permanently add useful items, consumables, pickups, mechanics, and characters to your save file. Most other unlocks are just okay in this regard. And then, some of them are putrid feculence that no player who is actually focused on winning should ever prioritize. If you want to get the coveted title of "Dead God", you need to unlock everything, but some make more sense to do before others. This is because the useful unlocks help you get other unlocks, while the unhelpful unlocks tend to take the place of the useful unlocks and actually make things more difficult. The purpose of this guide is to walk you through the general best unlocks, based on ease of difficulty as well as the quality of the unlocked item itself. It's also meant to warn you of the most deleterious items this game facetiously presents as "rewards" based on the same criteria. This guide works for new players (with the help of the game's wiki[bindingofisaacrebirth.wiki.gg]) as well as experienced players looking for their second or third Dead God off of a new save file.

Why Should You Trust Me?

I've been playing and watching Isaac for over half a decade at this point. I came from PS4 then moved to PC, and I have over a thousand hours of experience playing TBoI between them. Most importantly, I got Dead God without any gameplay altering mods, so I've personally done all of these unlocks already.
TLDR: I'm a really good and experienced player.

A Note About Hard Mode

There are two difficulties for regular Isaac runs outside of Easter eggs: Normal and Hard mode. Greed mode is its own thing. There are six unlocks that are locked behind Hard mode, and two of them have so many prerequisite unlocks that you likely won't get them until you've put hundreds of hours into the game. The rest of the unlocks can be gotten just fine on Normal mode.
The list of differences between Normal and Hard mode can be found here[bindingofisaacrebirth.wiki.gg]. Now, some people disagree, but I think, especially for a new player, Hard mode can make the game much more punishing. If you're struggling with any of the unlocks on this list, you may want to consider attempting them on Normal mode. However, you may already know the biggest consequence of this, that being Dead God requires all character unlocks to have been completed on the maximum difficulty, whether that be Hard mode or Greedier mode. This means that if you do a character's unlock on Normal mode and you plan on getting Dead God, you're eventually going to have to do it again. This may be worth it, since you'll have an additional great unlock for the second go-around, but it will be at the very least more time consuming.
It's ultimately up to you whether you want to do any of the following unlocks on Normal mode (besides Bethany). If you choose to do this, I'd strongly recommend you go back to the Normal mode unlocks you've gotten and do them on Hard mode before moving onto the unlocks that are not in The Good Ones. This is because those unlocks could actually make the game more difficult by cluttering the loot pool or adding some other garbage to the game (looking at you, Rotten Beggars). If you're gonna do something the Hard way, I'd say you should try to make it easier, as oxymoronic as that sounds.

Runes

You should make unlocking at least six runes a priority. Once six runes of any type are unlocked, rune shards, which are very weak and difficult to use effectively, stop spawning. The following runes are the six I would recommend the most based off of how good they are but also how easy they are to unlock.
Most of the challenge unlocks for these runes come around early enough. I'd recommend you refer back to this section as you're unlocking the items in the next section. You can do High Brow and Head Trauma right away.
Jera (Complete Challenge #2: High Brow)[bindingofisaacrebirth.wiki.gg]
This is definitely the best rune in the game when factoring in how easy it is to unlock. Jera is immensely powerful in the hands of a good player and can be used to break the game under the right circumstances.
Ehwaz (Complete Challenge #3: Head Trauma)[bindingofisaacrebirth.wiki.gg]
In my opinion, Ehwaz is greatly underrated. An uninformed player probably just thinks that it creates a trapdoor to the next floor most of the time and rarely creates a crawlspace instead, but they'd be incorrect. In reality, it creates a trapdoor to the next floor on any normal tile and a crawlspace (normally containing an item or a black market) on any tile with a decoration on it. You can probably guess which one I normally use Ehwaz for. The challenge isn't too bad and is unlocked by default.
Perthro (Complete Challenge #6: Solar System)[bindingofisaacrebirth.wiki.gg]
I won't lie, this is one of the more difficult challenges and it isn't unlocked by default either. However, its challenge unlock is easier than most in the game and you'll get it just by playing normally without having to go out of the way. What you get from completing it is a one-time use D6, which, trust me, you'll be glad to have.
Blank Rune & [bindingofisaacrebirth.wiki.gg]
Clear Rune (Complete Challenge #30: The Guardian)[bindingofisaacrebirth.wiki.gg]
You may be wondering why I'm recommending you unlock Blank Rune. Well, for starters, it is a direct upgrade over a rune shard since it both triggers a stronger version of the rune effect and has a chance to duplicate itself upon use. Unlocking Blank Rune is also the only way to gain access to Clear Rune, a rare but useful item that can be used to break the game. The challenge isn't too bad, in my opinion, and gets unlocked very early on.
Ansuz (Complete Challenge #5: The Tank)[bindingofisaacrebirth.wiki.gg]
You'll probably unlock The Tank early enough in the game just by doing a run or two as Magdalene. It's an easy enough challenge, if a bit boring, and Ansuz is an alright rune that gives you full mapping and shows where your secret rooms are. Pretty cool.
Algiz (Complete Challenge #8: Cat Got Your Tongue)[bindingofisaacrebirth.wiki.gg]
This challenge is quite tricky, but since you can unlock it fast just by becoming Guppy, I felt the need to include it on this list. Try using a controller for Cat Got Your Tongue if you own one, I think you'll have an easier time. It was between this, Hagalaz, and Berkano for the last spot here, and I thought that the latter two just lacked the utility that Algiz has. Algiz is not only useful as a defensive item for boss fights that will greatly aid you when playing as health lacking characters such as Keeper and The Lost, but it's also fantastic for health donation machines, devil beggars, and confessionals.
Bonus Unlock: Rune Bag (Defeat Isaac with Lilith)
This item will be quite good after getting the previous six. It's fine to unlock Cambion Conception afterwards.
Honorable Mention: Dagaz (Complete Challenge #4: Darkness Falls)[bindingofisaacrebirth.wiki.gg]
Dagaz is definitely a great rune and serves as one of the only ways to remove curses. That being said, unlocking Darkness Falls takes too long for me to put it in this section.

The Good Ones (Part 1)

I'll start off with the ones you can get earlier on and work my way towards the later game unlocks near the end.
Broken Modem (Complete seven daily challenges) &[bindingofisaacrebirth.wiki.gg]
Cracked Crown (Complete five daily challenges in a row; they don't have to be consecutive days)[bindingofisaacrebirth.wiki.gg]
Broken Modem is my favorite item in the entire game since it was buffed in Repentance. Whenever you pick up this item you are guaranteed to think to yourself "Thank you, Broken Modem!" at least once during your run because of the many helpful effects it has. Daily challenges are completely separate from the rest of the game in terms of unlocks, so you have no reason to not play a daily challenge every day until you unlock Broken Modem. While you're at it, try to get Cracked Crown as well; it's a really good stat trinket.
A Card Against Humanity (Complete Challenge #12: When Life Gives You Lemons)[bindingofisaacrebirth.wiki.gg]
This is a great and very easy unlock that can give you tons of pickups. There's a chance that it spawns Petrified Poop, which will make the remainder of its use even more potent. It's also very recognizable as a ground pickup so you can find it in shops easier than most cards. The challenge is unlocked by default so this should be a priority.
Burnt Penny (Complete Challenge #13: Beans!)
This is a super useful penny trinket with an easy challenge unlocked by default. Why not?
A bunch of stuff (Defeat Mom)
Killing Mom for the first time nets you a ton of unlocks.
Gold Heart (Complete Challenge #21: XXXXXXXXL)
Can get you some extra money, and the challenge is relatively easy, if a bit tedious.
Tech.5 (Complete Challenge #18: The Host)
The Host is quite an easy challenge that's unlocked by default and Tech.5 is a pretty good quality 3 item, so I think it earns a place here.
As of the latest Repentance+ patch, they've actually given Tech.5 what I consider to be a slight nerf which grants it a 5% chance to apply a Fruit Cake effect. Apparently this used to be the intended implementation of the item but was accidentally removed at some point. Since Fruit Cake has a small chance to shoot out an Ipecac tear, this also applies to Tech.5, meaning that you can damage yourself with Tech.5 unexpectedly and basically unavoidably. It's a very small chance, but as a result, I can't recommend picking this item up as either variant of The Lost as it can end your run. It's still a good item, though. I'd be excited to see it on all other characters.
Azazel (Take three Devil Deals in a single run)
You'll probably unlock him without actually trying to but I figured I'd mention him anyway. In my opinion, Azazel is the single most powerful character in the game. He is the character you'll normally want to use for non-character specific unlocks because of how powerful he is, and he is also required to unlock Satanic Bible.
Vurp! (Obtain 50 or more items in a single run)
Vurp! is a super powerful pill that respawns the last pill you used. It's most useful after you've already identified it, but it won't hurt your run at all after its first use either, even if the last pill you used was a Tears Down. You could eventually unlock this without trying at some point, but if a run is already a guaranteed success it couldn't hurt to grab a few more items in order to unlock Vurp! a bit earlier.
Planetarium (Collect three astral items in one run)
I'd link to what an astral item is if embeds worked properly. Planetariums are rare but can be very helpful; since their chance of spawning increases from 1% to 21% if you skip an item room, they can help fill in the gap from the occasional missed item (generally because of a lack of keys or time constraints).
Ace of Clubs (Win three times in a row)
You might get this one without trying but just in case you should try to do it as soon as you unlock Azazel as the game is going to get harder the longer you play it. Ace of Clubs is a pretty good card that can wipe a difficult room and give you a bunch of bombs.
Chaos Card (Complete Challenge #9: Demo Man)
This card single-handedly trivializes many difficult bosses in the game. It can come in as a run-winner if you manage to find it. The challenge itself is pretty easy.
Counterfeit Penny (Play the Shell/Hell Game 100 times)
At some point you're gonna have a ton of money to spend and nowhere to spend it except for a Shell Game. This is the time to unlock Counterfeit Penny, an excellent penny trinket that will greatly increase the amount of money of you gain.
Challenge #23: Blue Bomber (Blow up 10 tinted rocks and defeat Mom's Heart 11 times)
They have an "X" on them and get harder to see the lower the floor you're on. It's best to just use Azazel for this. Needed for the next unlock, and also happens to have an overlapping unlock condition with It Lives!.
Gold Bombs (Complete Challenge #23: Blue Bomber)
Infinite bombs! (for the floor)
Charged Key (Complete Challenge #33: Pokey Mans)
One of those special, easier unlocks that just makes your save file slightly better and has no downsides,
Mom's Knife (Defeat Satan with Isaac)
This is one of the most powerful tear replacement items in the game. It melts bosses and will win you runs.
Satanic Bible (Defeat Isaac with Azazel)
On top of being a run-winning health item that increases your odds of making deals, Satanic Bible works well with The Lost and Tainted Lost, unlike Book of Revelations.
Blood Bag (Use health donation machines 30 times)
If you're playing the game correctly you should unlock this one without trying. On top of giving you a health up, it restores four hearts (can refill the health you just donated) and augments your speed. Also, did you know that using Spindown Dice on Blood Bag turns it into Brimstone?
Store Upgrade Level 1 (Donate 20 coins to the donation machine)
Having a larger shop is going to benefit you greatly later on and the cost isn't that much all things considered.
Blank Card (Defeat Isaac with Eden)
It got nerfed pretty hard in Repentance. You can still break the game with it, though, and it has a pretty easy unlock condition.
Lucky Pennies (Donate two coins to the Greed Mode donation machine)
Outside of beating Greed Mode to begin with the barrier of entry to this very good unlock is quite low. Do this while getting the next unlock.
Lilith (Defeat Ultra Greed or Ultra Greedier with Azazel)
Lilith is necessary to unlock Incubus, C Section, and Twisted Pair, all of which are on this list.
Forget Me Now (Defeat Satan with ???)
A very solid item with a reasonably easy unlock condition, Forget Me Now also synergizes extremely well with 'M.
The Void (Defeat Hush)
Unlocking The Void as fast as possible is going to save you a lot of hassle later on for annoying Delirium unlocks due to the mercurial nature of the portal appearing or not. You're going to need to defeat Delirium to get list inhabitants Eden's Soul and D Infinity.
Incubus (Defeat Hush with Lilith)
Incubus is an incredibly powerful item that, in essence, doubles the amount of tears you put out with no downside aside from whatever cost you paid to get it. Make this your first Hush unlock.
Eve (Don't pick up any hearts for two consecutive floors)
Eve is necessary to unlock Athame.
Athame (Defeat Hush with Eve)
Gives enemies a luck based chance for enemies to explode into black rings of death when you kill them. A really good Devil Deal item.

The Good Ones (Part 2)

Downpour (Defeat Hush three times)
You're gonna need this to get to Mother. You should need one more Hush kill at this point, which you can do with Isaac and then go to The Void right after.
Delirious (Defeat Delirium)
This item was buffed in Repentance+ and is now quite powerful. It was a mandatory unlock before anyway in spite of its limited usefulness, so it's good that I can now add it to the list as an official top tier unlock. You can get this unlock while doing the next one.
D Infinity (Defeat Delirium with Isaac)
This is the best dice item in the game. Its versatility is simply unmatched. 100% a run-winner that you should prioritize unlocking as soon as you defeat Hush.
Eden's Soul (Defeat Delirium with Eden)
This is a lot of people's favorite 12 charge active item and for good reason. It gives you two items from whatever item pool you're currently occupying, which is incredibly strong for an active item. Did I mention it synergizes very well with 'M?
Magdalene (Have seven or more heart containers at once)
You'll almost certainly get this without trying. Magdalene is required for the next two unlocks.
Credit Card (Complete Challenge #10: Cursed!)
This is a great card that can get you free items from the shop and devil deal. The only caveat is that it's pretty rare. I consider the requisite challenge to be quite easy as long as you remember to use Yum Heart when it's off cooldown.
Eucharist (Defeat Delirium with Magdalene)
Yet another great Delirium unlock with an easy character, Eucharist functions the same as Goat Head except it only makes angel rooms show up. Since angel deals are free unlike devil deals, you could argue that Eucharist is actually the better item. It will likely replace another, more immediately useful angel pool item when you find it but will more than make up for that with the items it gives you access to for the rest of your run.
Strange Door & Jacob & Esau (Defeat Mother)
The Strange Door is, in my opinion, the single most important unlock in the game. It opens the way to the game's final ending, so if you're just trying to "beat" the game it will be your last unlock before you do that. It's also required to unlock every tainted character in the game, many of which have S tier unlocks. Jacob & Esau allow you to unlock The Stairway and Birthright. You can get this unlock while doing the next one.
'M (Defeat Mother with Eden)
Fun fact: I believe this was my last (or at least close to last) normal character Mother unlock. I massively underestimated this trinket. Don't be like me. This is definitely one of the best trinkets in the game and can turn a bad active item into an extremely powerful one out of the blue, such as an R Key. On top of that, you can just drop it when you're satisfied and don't want to reroll anymore. Make this your first Mother unlock.
Spirit Sword (Complete Challenge #39: Isaac's Awakening)
Spirit Sword can win you some runs on certain characters but it's definitely not good for all of them (both variants of The Lost being key examples). It's worth unlocking for the ones that can take advantage of it. The challenge is a little difficult but nothing unbearable.
The D6 (Defeat Isaac with ???)
On top of being a direct upgrade for Isaac, this is one of the best active items in the game for any character that will improve the quality of your other items. Technically this can be unlocked before The Polaroid, but since you can unlock The D6 while doing the next unlock if you unlock The Polaroid first, I opted to put it here.
Bloody Lust (Defeat Isaac with Samson)
A solid per floor damage up that you can exploit with various health donation mechanics.
The Polaroid (Defeat Isaac five times)
Necessary to access Chest, which opens the way to all ??? unlocks, including Birthright and Blessed Penny. You should probably prioritize unlocking The Polaroid over The Negative, since Chest is an easier floor to complete than Dark Room. If you've been following the guide and finished the Runes section, this should be unlocked by now.
Fate (Defeat ??? with ???)
Pretty underrated unlock, in my opinion. It gives you flight and an eternal heart. Flight does a lot of useful stuff, such as invalidating floor obstacles and sparing some of your health when accessing a Curse Room. Azazel is the best character in the game mostly because he has flight. The more you can improve your chances of getting flight during a run the better. The fact that you can easily get Fate after unlocking The D6 lands it a place on this list.
Bomb Bag (Defeat Satan with Cain)
Gives you bombs. Around 10% of the time it'll be a troll bomb; keep that in mind.
The Negative (Defeat Satan five times)
Necessary to access Dark Room, which opens the way to all The Lamb unlocks, including Missing Poster, Curved Horn, The Soul, and Damocles.
Curved Horn (Defeat The Lamb with Judas)
This is one of the best trinkets in the game. Its simple damage up is incredibly powerful. Get this along with the next unlock.
Gulp! (Complete a Victory Lap by defeating The Lamb)
Select "Yes" once you defeat The Lamb. Defeat