After playing so much Enter the Gungeon, I truly forgot how frustrating Binding of Isaac can be.
Reach the end of the second floor, but the game hasn't given me a single key, so I can't get to the 2nd floor powerup room. Restart
Reach the 3rd floor with no good powerups. Restart
Get two utterly useless powerups on the first floor. Restart
It happens way too often, where it makes more sense to restart because the first few floors give me jack shit, rather than continuing a run that is now more difficult because I have an underpowered character.
I can only think of a number of times I had to restart a Gungeon run, and usually it's because I wasn't playing too well.