Spinoffs included? Avalanche. Maybe I just suck at Puyo Puyo, but I can't beat it.
Spinoffs not included? Dreamland on Hard Mode. It's not that it's actually that hard, but it's the only one where you can't just bullshit through whatever the game throws at you with copy abilities.
To get 100%, I'd say Canvas Curse.
FUCK Paint Panic. And the other mini-games to a lesser extent. Not to mention you have to beat every level 5 times, once with each character.