Ascend 20

Complete Ascension Level 20, the top of the mountain, with any one character. You reach it by winning at each Ascension level from 11 through 20 on that character (A20 famously adds a brutal double Act-boss fight among other things), so it's the single biggest time-and-skill sink on the list. Only a standard Act 3 win at A20 is needed, not the true ending. Do it on whichever class you've mastered - Ironclad and Defect are the popular, forgiving picks. Take your time; nothing here is missable so you can grind the climb run by run.