Little anecdote: never have I heard from so many of my male friends that they cried during a movie than with Grave of the Firelies. Beautiful gem.That depends on who your asking and what they specifically want from an anime in general. If we're talking in terms of mainstream critical acclaim(not popularity) Some would say Cowboy Bebop or Trigun. Others would pick movies like Ghost in the Shell 1995 or Akira or Grave of the firelies. There are those who would put the original Gundam 0079 up there.
For me, i can't really pick. There are too many i've seen. My favorite manga of all time though is Chrno Crusade. It has a sense of adventure and starts out fairly innocuously, but keeps on building to the point where there is nothing else to call it but a masterpiece of writing and fleshed out human like characters.
Wish there was an anime of it.
I need to watch Akira fully someday. Only saw parts of it as a kid.