Homer -- John Goodman (Homer is just a mentally challenged Fred Flindstone anyway) -- Second Choice: Ed Harris -- pefect Homer head
Marge -- Shelly Duvall -- She did a great Olive Oyl in the live-action Popeye Second chice: The Dude that plays Robert's wife in Everybody loves Raymond
Bart : Cauley McCulkin -- the perfect Bart -- a kid trapped in a man's body or is it vice versa? (Bart is in his 20's after all). Second Choice -- David Spade (his experience on Dickie Roberts would be a plus).
Lisa -- Any generic Hollywood girl brat will suffice. Let's say, the kid from Uptown Girl.
Maggie -- Use Elizabeth Taylor (she was the original voice of Maggie after all).
Groudskeeper Willie -- Mike Myers (since he loves playing the scotsman) or James Doohan (if he can still walk).
Otto -- Keanu Reeves -- almost a brainless as the Otto character himself. Whoa Dude! I know Kung Fu!
Moe -- Tony Shaloub
Nelson -- That kid from the Public Service announcement on Bullying
Mr. Burns -- Gary Oldman -- good bone structure for the part -- also likes to play crazy old men.
Abe -- Peter Boyle -- good at playing cranky/crazy old men
T.H.H. -- A live action Simpsons could actually work.
;)