SPEED!

SPEED! is Challenge #22. In this challenge, all enemies are sped up as if under the "speed up" effect of the Broken Watch. Isaac also has greatly increased movement speed as well. The goal is to defeat Mom's Heart or It Lives with a "soft" time limit of 16 minutes.

Difficulty

This is arguably one of the hardest challenges in the game, for two major reasons. Firstly, the increased speed for both the enemies and Isaac can make most routine rooms and bosses challenging. More importantly, the 16-minute soft time limit is also very hard to beat and may force the player to forgo exploring for rewards that might have helped them later on. Note that the time limit is not a "hard" one and that the game is not over when the countdown timer reaches 0; however, from that point onwards Isaac will start taking half a heart of damage every 10 seconds, or a full heart of damage starting from chapter 4.

Strategy

General

Health is always important, but even more so in this challenge. Not only will health compensate for the damage taken, be it from the more difficult rooms/bosses or the timed damage, but it can also be used for Devil Deals to access its high DPS item pool. Items that generates health or protection thus help greatly, These include The Wafer, Cancer, Yum Heart, Unicorn Stump, Prayer Card, and many many more.
Blank Card is a powerful item in this run, as there are cards and runes such as "The Emperor", "The Sun", "Ansuz", and "Ehwaz" which can allow both faster progression through the game. Certain cards and runes such as, "The Hierophant", "The Lovers ", "The Chariot", "The Sun", "Algiz", and "Dagaz" can also act as health regeneration or protection to counteract the timed damage or the increased difficulty in general.
Getting the Stop Watch will make this challenge easier, since it will slow all enemies in the room when Isaac takes damage, counteracting their increased speed.
The Ludovico Technique shouldn't be picked up without high shot speed, as it will move slower than most enemies.
Since Isaac starts with increased speed, Taurus can be used to start every room with the My Little Unicorn effect making it effective for clearing rooms quickly. The invincibility from it can also block timed damage occasionally.
The Bible can be used to instantly kill Mom and It Lives, making it a more valuable item in this run. In the same vein, Plan C is also useful, though only against the final boss.
Clicker can be used to change Isaac into a more powerful character such as Azazel or The Forgotten, allowing the player to clear rooms more quickly.

Speed run

The adverse effect of not finishing the run in within 16 minutes (periodic damage every 10 seconds) can be simply avoided by beating the timer.

If the player wishes to beat the timer, it might be a good idea to cut down exploring to a minimum. Find and visit the Treasure Room, occasionally the shop, and the boss, then move on as soon as possible. The Compass, the Crystal Ball and The Mind are very useful if this is the desired strategy, as is "The Emperor" card. Floor skipping with We Need To Go Deeper! and such are also valuable time-savers, as long as the player is confident with their current set of items.
Isaac's highly increased speed is a powerful asset to rapidly completing this run but can be dangerous as the player may accidentally run over spikes or into enemies/bullets that they otherwise would not run into. It is important to be careful and adjust to the speed-up.
Anything that could help to clear rooms faster is going to alleviate some of the difficulty of this challenge. Damage and Tear boosting items are thus a potential priority, making Devil Deals desirable because of their DPS heavy item pool. "Room clearer" items such as Toxic Shock and "Boss killer" items such as Head of Krampus are also very useful for speeding up progress.
Avoid Challenge Up (i.e. Purple Heart, Champion Belt) since Champion enemies are not only much harder to kill, they will also take much longer to kill, and the player is already short on time.
Boss Rush is likely to appear on this challenge if the player is trying to beat the timer, but it should be avoided unless there is a way to teleport out of it or skip it.
Using bombs for damage or skipping rooms might be necessary if one wishes to beat the timer. Automatically-replenishing explosives (Ipecac, Dr. Fetus, etc.) will greatly aid the player in being to do this.
Black Candle is a valuable item to purchase from the shop, as it prevents Isaac from being afflicted by Curse of the Lost and Curse of the Maze, both of which can waste precious time. The Dagaz rune will also remove curses for a single floor if used.
Error: The given collectible ("Teleport") does not exist., if used wisely, can save a lot of exploration time by teleporting whenever Isaac doesn't appear to be near rooms of interest. This will inevitably cut down the number of rooms that the player needs to explore.

Slow and Steady

After 16 minutes, the periodic damage taken every 10 seconds can be counteracted by generating enough health or obtaining enough protection against said damage.

The timed damage can be absorbed by the Holy Mantle, making it an even more valuable asset since Isaac can leave the just-cleared room the way he came, re-enter it, wait until the timed damage is dealt, and proceed. By doing so, Isaac can get a 20-second buffer (10s if hit) to rinse and repeat the process without taking any damage.
Pyromaniac and explosives (Curse of the Tower or any other way to get a lot of bombs) allows Isaac to survive long after the 16-minute limit, and in the case of Pyromaniac with automatically-replenishing explosives such as Error: The given collectible ("No. 2") does not exist., very likely the entirety of the run.
Guppy's Paw in the late game can potentially give the player up to 6 minutes of borrowed time, 12 minutes with The Wafer, and even more if the player happens to find HP upgrades in the final moments of the run.
Isaac's Heart makes Isaac completely immune to the timed damage. However, because of the increased speed of your player and enemies, beware that dodging may be more difficult.
Several Sharp Plug + The Wafer/Cancer combos will also allow effectively infinite health.
Items that grant health or protection on hit such as Old Bandage, Gimpy, Virgo, and Celtic Cross are useful for surviving past the timer in general.
- The items above are also more effective when in possession alongside Dull Razor.

Notes

Before a patch, Isaac moved at normal speed while all enemies moved faster. It was changed to give Isaac increased speed, as the challenge was deemed to be unfairly difficult before.