Otherwise a very standard run, the challenge comes from every single enemy and boss placed naturally in rooms (as opposed to being spawned later) being doubled. Due to the high enemy density damage may prove difficult to avoid in some rooms. It is recommended for oneself to be already familiar with the gameplay of Jacob and Esau prior to attempting this challenge.
While room clearing items like Toxic Shock and items synergizing well with 20/20 such as Jacob's Ladder can be incredibly useful, obtaining them will be difficult with no spawning Treasure Rooms.
As Esau begins the challenge with X-Ray Vision, Secret Rooms are instantly revealed, which may provide Jacob and Esau with helpful resources.
As in most challenges, Angel and Devil Rooms can help make up for a lack of treasure rooms, though gaining access to them may be difficult due to the nature of the challenge.
Using Genesis will remove items for both Jacob and Esau, but will only produce an amount of items equal to the inventory of the brother who activated the item. However, it will grant both an additional 20/20, resulting in the pair firing 3 tears per shot with no further damage down. If obtained, it is thus recommended to use Genesis as early as possible in the run to avoid losing too many items.
It may be wise to keep Silver Dollar if found, as the Shops it will spawn in Chapter 4 can be incredibly useful.
Eraser is an extremely powerful item for this challenge that can be found in Shops, as permanently erasing common enemies can help tremendously.
Mapping effects such as The Compass or The Mind can help quickly navigate through levels and avoid unnecessary risks.
Teleportation items such as 0 - The Fool, Teleport!, or Telepills can be used to quickly escape dangerous situations or skip rooms altogether. Glowing Hour Glass may also be used to return to the previous room and revert any possible health loss.
Room clearing effects are particularly powerful in this challenge: