Challenges

Challenges are unique runs in the game. Isaac typically starts each challenge with one or more specific items which makes 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. Players, with the advent of modding, have created their own Custom Challenges too.

General Strategy
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.
 * If other players join the game in the first room for true co-op, they will not get to select a character and will be forced to play as the character the challenge has you play as, ex. for Blue Bomber, all players will be forced to play as no matter what. (This excludes untrue co-op because of co-op babies.)
 * 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.
 * 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.
 * 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 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, , and are therefore highly useful items.
 * ,, and are also useful for blindfolded challenges, since they recharge based on a timer, rather than an amount of cleared rooms.
 * can allow Isaac to change into, whose overrides the blindfolded effect by default.
 * Some spacebar items like can be really helpful, providing an alternative method of dealing damage.
 * 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.
 * In some longer challenges (e.g. XXXXXXXXL), using a Sacrifice Room until it teleports Isaac to the Dark Room is a viable strategy. Once in the Dark Room, the trophy can be spawned by defeating The Lamb.
 * In a similar vein, all runs can be completed by killing Delirium, meaning that the player can beat a challenge through an alternative method such as defeating Hush then traveling to The Void; however, this is generally extremely difficult given the restrictions challenges place on the player.