Monkey Island 4.
Maybe Grim Fandango, but I haven't played that much yet.
I like the new 3D engine for the monkey series, makes it more playable in my opinion (Grim Fandango is the same). Very easy to control, it's much better than point and click anyway.
Can't remember much about the ending on Monkey 4 since it's been a while since I last played it, but I highly recommend it to anyone.
If you are talking about conventional point-and-click adventures I'd have to say Sam & Max Hit the Road or Day of the Tentacle.