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Challenges are unique runs in the game. Isaac typically starts each challenge with one or more specific items which make normal play more difficult. With few exceptions, Treasure Rooms are not available during challenges. Each challenge unlocks new content for the game, such as runes when completed.
Most challenges are designed to increase the difficulty of the game in a unique fashion. This doesn't mean all challenges are difficult, however; challenges like Computer Savvy are quite easy to beat. Some challenges do compensate for this by being especially punishing; Solar System is a good example of this. Each challenge has certain strategies that can be employed to make the run easier. However, there are a few strategies that can apply to all challenges.
- Challenges can be played in co-op, allowing a second player to contribute to the run without being hindered in the same way Isaac is. This is especially useful in any challenge where Isaac is Blindfolded, as the second player will be allowed to fire tears normally.
- Due to the lack of Treasure Rooms, Devil Rooms become much more valuable. Some challenges can be made much easier by making just one deal, but it is worth noting that other challenges reduce Isaac's health to the extent that Devil Deals become too risky.
- Some rooms (including Crawl Spaces) may have Treasure Room items by default. Since these items are random, results can vary from run to run.
- Because locked Treasure Rooms won't spawn, keys can be used far more liberally. Also, trinkets and items that generate more coins, along with upgraded Shops, can help Isaac acquire a greater range of powerful items.
- The Bible instantly kills Mom and Mom's Heart / It Lives. All challenges require defeating Mom, and most require defeating Mom's Heart or It Lives, making this an extremely powerful item, especially in challenges where Mom or Mom's Heart / It Lives is the final boss.
- Pandora's Box will spawn The Bible if used in Womb II, Utero II, or Scarred Womb II, making it a reliable way to acquire The Bible.
- Curse Rooms can spawn items, making them valuable.
- In some challenges, Dice Rooms and the D4 are very useful, allowing that challenge's starting items to be rerolled, thus removing most of the difficulty. NOTE: This changes depending on the challenge. Most challenge pages contain details on the results of rerolling.
- Butter! can also remove starter items.
- Blindfolded challenges are arguably the most difficult challenges due to Isaac's inability to fire tears. There are several methods to work around this.
- Familiars can provide an alternative method of dealing damage. Powerful familiars like Daddy Longlegs, Lil Brimstone, and Incubus are therefore highly useful items.
- The Boomerang, The Candle, and Red Candle are also useful for blindfolded challenges, since they recharge based on a timer, rather than an amount of cleared rooms.
- Clicker can allow Isaac to change into Lilith, whose Incubus overrides the blindfolded effect by default.
- Some spacebar items like Tammy's Head can be really helpful, providing an alternative method of dealing damage.
- Chaos is a powerful item in challenges, as it can allow powerful items to be found more commonly, such as in the Shop or after defeating bosses.
- Defeating a boss beyond the specified end of the challenge (e.g. defeating Mom's Heart when the goal is to defeat Mom) will still spawn the trophy.
- Apart from the achievement related to beating the challenge, all achievements are locked. Also, no Donation Machines will appear in any challenge.
- The challenge reward will not be unlocked unless the trophy is picked up. If a Devil Room or Angel Room appears allowing Isaac to go to Sheol or the Cathedral, the unlock will be forfeited.
- Isaac will not start any challenge with The D6.
|1. Pitch Black||
|Default||Rune of Hagalaz|
|2. High Brow||
|Default||Rune of Jera|
|3. Head Trauma||
|Default||Rune of Ehwaz|
|4. Darkness Falls||
|Defeat Mom's Heart 11 times||Rune of Dagaz|
|5. The Tank||
|Have 7 or more Red Heart containers at one time||Rune of Ansuz|
|6. Solar System||
|/||Defeat Mom's Heart 3 times||Rune of Perthro|
|7. Suicide King||
|Defeat Mom's Heart 11 times||Suicide King|
|8. Cat Got Your Tongue||
|Become Guppy||Rune of Algiz|
|9. Demo Man||
|/||Defeat Mom's Heart 9 times||Chaos Card|
|Have 7 or more Red Heart Containers at one time||Credit Card|
|11. Glass Cannon||
|Beat The Family Man (challenge #19) and defeat Lokii||Rules Card|
|12. When Life Gives You Lemons||
|Default||Card Against Humanity|
|14. It's in the Cards||
|Default||SMB Super Fan|
|15. Slow Roll||
|16. Computer Savvy||
|17. Waka Waka||
|18. The Host||
|19. The Family Man||
|Pick up both Key Pieces from the Angels in one run||Epic Fetus|
|/||Defeat Mom||Rune of Berkano|
|/||Defeat Mom||Gold Heart|
within 16 minutes, otherwise under constant periodic damage every 10 seconds.
|Defeat Mom||Get out of Jail Free Card|
|23. Blue Bomber||
|Destroy 10 Tinted Rocks and defeat Mom's Heart 11 times||Gold Bomb|
|24. PAY TO PLAY||
|Defeat Isaac as Cain||2 new pills|
|25. Have a Heart||
|/||Defeat Mom||2 new pills|
|Defeat Isaac 5 times||Stud Finder|
|28. PRIDE DAY!||
|29. Onan's Streak||
|Defeat Mom||Kidney Stone|
|30. The Guardian||
|/||Defeat Mom||Blank Rune|
|The Basement/ The Cellar/ [[Burning||Defeat ??? or The Lamb||Laz Bleeds More!|
|32. Aprils Fool||/||Defeat Mom||Maggy Now Holds a Pill!|
|33. Pokey Mans||
|Defeat Mom's Heart 11 times||Charged Key|
|34. Ultra Hard||
|Defeat ??? or The Lamb. Possession of The Polaroid/ The Negative is required, prohibiting getting to Dark Room through a Sacrifice Room.||Samson Feels Healthy!|
|Defeat Isaac 5 times||Greed's Gullet|
|1.||Pitch Black||2.||High Brow||3.||Head Trauma||4.||Darkness Falls||5.||The Tank||6.||Solar System||7.||Suicide King||8.||Cat Got Your Tongue|
|9.||Demo Man||10.||Cursed!||11.||Glass Cannon||12.||When Life Gives You Lemons||13.||Beans!||14.||It's in the Cards||15.||Slow Roll||16.||Computer Savvy|
|17.||Waka Waka||18.||The Host||19.||The Family Man||20.||Purist|
|21.||XXXXXXXXL||22.||SPEED!||23.||Blue Bomber||24.||PAY TO PLAY||25.||Have a Heart||26.||I RULE!||27.||BRAINS!||28.||PRIDE DAY!|
|29.||Onan's Streak||30.||The Guardian|
|31.||Backasswards||32.||Aprils Fool||33.||Pokey Mans||34.||Ultra Hard||35.||Pong|
|The Binding of Isaac: Rebirth|
|Achievements||Attributes||Bosses||Cards and Runes||Challenges||Chapters|