All your progress won’t mean anything, basically, and new characters can’t be earned. There’s a big drawback to using mods though - enabling a mod will turn-off achievements and unlocks in-game. Instead of slogging through the main game and hoping the RNG rewards you with great loot, many players opt to use Steam Workshop mods to make things easier.
The Binding of Isaac: Rebirth just received another DLC upgrade that, surprise-surprise, makes a difficult game even harder.
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