Though risky, the Boss Rush and ??? will both provide additional chances at good items.
As a result of beginning the challenge with both Key Pieces, Angel Rooms are much more likely to appear than normal. Due to Angel Room items being generally more useful, it is advised to avoid Devil Rooms altogether.
It is somewhat easier to beat this challenge with The Polaroid (which doesn't appear after the Mom fight in Afterbirth †) than it is with The Negative, as Isaac is an easier fight than Satan in this challenge. Furthermore, the Chest can provide many chances at useful items that the Dark Room does not.
The Red Chests in the Dark Room now offer Devil Deals, granting powerful items at the cost of Red Heart Containers.
Aside from beating ??? or The Lamb for the first time, the player must also unlock all starter items in the challenge. (Access to Key Pieces, Mom's Knife, etc.)
Despite being forced to take The Negative, the Cathedral can still be accessed; however, once Isaac is defeated and the chest is entered, the run will simply end and will not count as a completion of the challenge.
If the player starts the challenge before The Polaroid and The Negative have been unlocked (using I AM ERROR, a sacrifice room, We Need To Go Deeper!, etc.) then the player will need to repeat said method or use another method to advance to Mega Satan.
Killing Delirium will count as completing the challenge.