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  • Anti-Climax Boss: While The Witness, the final boss of the Alternate Route, is undeniably an awesome boss, it lacks one thing that the true final bosses from Afterbirth and Afterbirth+ had: scaling damage resistance, making her more of a glass cannon compared to other final bosses. Because of this, it's possible to steamroll through it with the right items; for example, a familiar that can home in on and attack enemies, like a Level 3 or 4 Meat Boy. Worse, if you managed to even get to it in the first place, chances are you're powerful enough to just stamp through, so steamrolls are more likely than a true Climax Boss fight. The fight was made much more impressive in Repentance by making the arena much smaller and giving the boss damage scaling.
  • Best Boss Ever:
    • The final boss of the Alternate Route, The Witness, an undead Mama Gurdy. The mod drops all pretenses and flat-out indulges in insane Bullet Hell, with grids of bullets, lasers, shock waves, and enemy summons. And once you've depleted its health, the boss' head bursts out of its body and keeps attacking!
    • As far as regular bosses go, the Rotgut is pretty awesome too. It starts out normal enough, with you fighting a Sarlacc-esque monster that has admittedly tricky-to-dodge attacks, but once you deplete its health, it sucks you into it and the fight continues inside of it, in a 2D Crawl-space battle! First, you have to kill a giant maggot inside of it, and then you have to kill its heart; killing both causes it to spit you back out, and ends the fight.
    • The Visage is another well-liked battle for being a very well-executed Dual Boss. The two parts of The Visage will fight you in tandem and interact with each other in a lot of their attacks, and unlike Mask of Infamy, you have to constantly deal with both of them instead of simply defeating them one at a time and the Heart actually puts up a good fight with a number of tricky attacks across three phases.
  • Difficulty Spike: The alternate chapters introduced by the mod are much harder than their counterparts in the base game. This comes with the reward of item rooms always having two items to pick from. The bosses are a big step up from the base game, since most of them engage in intense Bullet Hell or have fast attacks. Which is why in Repentance, accessing the alternate floors requires defeating HUSH 3 times.
  • Ensemble Dark Horse: While most of the bosses introduced by the mod are well-liked for being creative and unique, some stand out more than others.
    • The Rainmaker, the flamenco-dancing, water-bending poltergeist boss, earned quite a few fans for his quirkiness. Being adorable also helps. He's so likable, Edmund said he wanted to cut him from Repentance for not fitting the Isaac universe but couldn't bring himself to do it.
    • The Siren earned a fair amount of popularity, partly for her for her unique gimmick of stealing your familiars and partly due to being deemed a Cute Monster Girl by players.
    • The Scourge is gaining a following for its Ugly Cute design and tricky fight.
  • Game-Breaker:
    • The Red Key. Using it can create an entirely new room. This room can be anything from a regular enemy-filled room, to an item room (even on floors where they wouldn't normally spawn), to a Devil Deal, and so on. By creating enough rooms to leave an invisible 13 x 13 grid, the player can even create an I AM ERROR room, and skip to the next floor note . The real kicker comes in when you do this in The Chest or the Dark Room, which resets the floor, allowing the player to get more items and repeat the process, ad infinitum. Sure, this item might be buggy, but it's probably the biggest Game-Breaker in this mod.
    • Magic Skin uses up a Heart Container to generate items. The heart is replaced by a broken heart that cannot be replaced by other pickups, essentially lowering your maximum health. However, if you play as The Lost, you can use Magic Skin to get every single item in the entire game, as he cannot gain broken hearts due to a lack of health.
    • Rock Bottom. Having it prevents any of your stats from being lowered, allowing for items like Ipecac or Soy Milk to be a lot more powerful than usual if picked up in the right order — which leads to complete game breaks if any tear modifying item is picked up after Ipecac is, due to not losing the +40 damage increase.
  • Genius Bonus: Like the original Isaac, this mod is full of this:
    • Akeldama, which is unlocked by Judas after defeating The Witness, is a pile of entrails that lets Isaac leave a trail of bloody tears that hit foes. It's a reference to Judas' suicide in The Bible: he hung himself in Akeldama, and when he died, his organs spilled out of his body.
    • Donkey Jawbone, a new item unlocked by defeating The Witness with Samson, is a nod to a story from the Bible in which the mythological Samson used a jawbone exactly like it to kill a thousand Philistines.
    • Also in the Bible, there's the story of how Jacob tricked Esau by offering him a delicious stew in exchange for the birthright to their dying father's possessions. In the game, Red Stew gives a short-term benefit (refills health and provides a great, but temporary, damage boost), while Birthright has a different permanent effect depending on the character that picks it up. In the case of Jacob and Esau, the one who picks it up copies three of the other's passive items.
  • Hilarious in Hindsight: About a year after Antibirth released its "two characters in one" package of Jacob and Esau, The Binding of Isaac: Afterbirth+’s final official update included its own "two characters in one" package in the form of The Forgotten and The Soul. The major difference is that Jacob and Esau requires controlling both characters simultaneously and both differ from the rest of the cast primarily in terms of stats, while The Forgotten and The Soul function more like a Tag Team and have individual quirks that make them much more different from other characters even beyond the "two in one" aspect. Then Repentance was announced and brought Jacob and Esau into Rebirth proper.
  • That One Attack: Baby Plum has an attack where it spews a continuous stream of bullets while propelling itself in the other direction at high speed, bouncing off of walls. This attack leaves you with very little room to dodge, especially considering that Baby Plum is a Basement boss.
    • One of the Scourge's attacks has it sucking in bullets from the walls of the room, forming a dense pattern for the player to dodge. The catch is that this attack also sucks in the player themselves, restricting movement and making it harder to avoid getting hit.
    • The Whitness has an infamous attack in which it shoots out a single tear that explodes into a Brimstone laser that rotates towards Isaac. The laser moves exetremely quickly, so if you did not take enough speed buffs, the attack is pretty much unavoidable.
  • That One Boss: The Heretic is an advanced form of The Haunt, and he lives up to his predecessor's reputation and then some. He starts the fight sending five flunkies with homing bullets at you — potentially annoying, but not difficult. But when they go down, The Heretic himself starts attacking, and pain ensues. He can charge at you repeatedly from alternating sides of the room for a full heart of damage, and to make things worse, he will home in on you slightly and can fake you out on the last charge. In addition, he can rain homing explosive tears at you from above, and possesses a Brimstone attack that bounces between the fireplaces in his boss room and will likely take up most of the room. It's not uncommon for players to leave the fight with five or six hearts less than they had when they entered.
  • That One Sidequest: The Bloody Mary challenge. You start as Bethany with Book of Belial instead of Virtues, Anemic, Blood Bag for extra starting health and speed, Child's Heart to increase red heart spawns, and there's no treasure rooms. Doesn't sound too bad? Well, you're also given Blood Oath, which reduces your red heart count to just half at the start of every single floor except the first. This would not be a problem for any other character due to soul hearts not being depleted, except Bethany cannot add soul hearts to her health. Or black or immortal hearts. This means that you're effectively a One-Hit-Point Wonder starting in Basement II and must pray to the random number generator that you'll get some kind of red heart pickup, and pray again after advancing to the next stage, and so on. Due to a bug, picking up any rotten hearts all-but guarantees death at the start of the next floor, due to the way Blood Oath's health subtraction does not take into account the fact that rotten hearts are always lost in terms of whole hearts, never halves. The goal of this challenge is Satan.


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