Take a character from a TV show or movie and replace them with a similar character from another show or movie:
Replace Sgt. Carter in Gomer Pyle, USMC with the drill instructor from Full Metal Jacket.
Take the alien from E.T. - The Extra-Terrestrial and replace him with the alien from, uh, Alien.
You get the idea.
Replace Dr Carter from ER with Dr Dorian aka ‘Bamby’ from Scrubs.
Replace Dr Becker with Sam Maloney.
Replace Frasier with Sideshow Bob.
I’ll clarify: not looking for the same actor playing different roles, but similar roles played by different actors.
Replace Emperor Palpatine with Emperor Ming the Merciless - result: ROTJ just got a whole lot better. Evil Eyebrows!
I knew that. but I got sidetracked.
No harm done!
Replace Carol Brady with Malcolm’s mom
Replace Monica (or Rachel or Phoebe) with Grace
Replace Naomi Wildman with River
Replace any one of the Charmed sisters with Willow
Replace Capt Bragen with Barney Miller
“Malone”, not “Maloney”
Replace Det Stabler with Det Columbo (or vice versa)
Replace Frasier Crane with Bob Hartley
Replace Captain Kirk with Captain Crunch.
I LIKE this game
I’ll stop now and let others play 
Last one tonight. I promise
Replace Dread Pirate Roberts with Captain Jack Sparrow
Replace Capt. Archer with Capt. Reynolds. Make three more seasons.
Replace Kramer with Lenny and/or Squiggy.
Replace Carol (BNS) with Karen (W&G)
ah yes, but who would be in charge? Roddenberry’s disciples (sp?) or Joss?
The casts of Will & Grace, Seinfeld, and Friends are totally interchangable:
Replace Grace with Elaine or Rachel.
Replace Will with Jerry or Chandler.
Replace Jack with Kramer or Joey.
They all are stereotypes.
What about Karen?
Replace Junior Soprano with Don Correlone (sp?)