Spencer Reid’s crazy mother on Criminal Minds and Charlie Harper’s therapist on 2 1/2 Men? Jane Lynch of Glee.
ETA: Yes, Fran Drescher did reprise her Spinal Tap role of Bobbie Fleckman on the Nanny. She Bobbie) was accompanying Brian Seltzer on his tour, and it turns out Bobbie & Maxwell Sheffield had met each other years ago in London.
David Morse, who played The Green Mile’s good cop Brutus “Brutal” Howell, later played bad cop Michael Tritter on House.
I’ve always loved the line when original Becky makes her “re-debut” appearance. Roseanne sees her coming into the house and says, “Where the hell have you been? It feels like you’ve been gone for three years!”
Actually, according to IMDB, his first role was a couple years earlier in Monaco Forever. He was Gay Karate Man.
David Morse was all over the place. He was a memorable hitman in the otherwise forgettable The Getaway - the Alec Baldwin / Kim Basinger version.
He was the pilot in The Langoliers.
He was also the red-haired ponytailed guy who released the virus in 12 Monkeys.
In another Roseanne degree of separation, Johnny Galecki played Rusty on the National Lampoon’s Christmas Vacation.
I’ll say this, just in case I missed an earlier post.
I loved Matthew Gray Gublerin The Aquatic Life with Steve Zissou". He was billed as “Intern #1”.
Something I just noticed: I was looking at Pippin’s song from Return of the King when who should I notice playing Denethor? Why, it was Walter Bishop from Fringe, aka John Noble!
He was also one of the main characters (Dr. Jack Morrison) in “Saint Elsewhere.” I just took a peek at his IMDB page to find that name, and he’s been in EVERYTHING.
Zoinks, when we started watching “Fringe,” I had to go look up John Noble because he looked so familiar. I love his Walter Bishop character so much.
Crazy like a fox, then. 
Couple more:
I always thought Orson Welles only sold wine. I had no idea what he did to become famous until I took film classes.
In the final scene of Top Gun, the pilot Tom Cruise goes to rescue is Tim Robbins, pre-Bull Durham. Even though he has a bunch of speaking lines, you can’t recognize him because of his flight mask. The only clear shot you get of his face is when everybody comes on the deck to congratulate Maverick.
Damn near the entire cast of American Graffiti
Damn near the entire cast of Lords of Flatbush
Damn near the entire cast of Uncommon Women and Others
Ally McBeal’s daughter went on to become Claire Bennett in Heroes.
This is the role I was going to mention, except that it stuck with me so much that I had major cognitive dissonance the first time I saw him in a “bad guy” role. These days I’m more used to it, but it was tough disconnecting the “nice doctor” image at first.
One I like is from the comedy/action film Hot Fuzz. The lead character, a cop named Nick Angel (played by Simon Pegg), is really wrapped up in his work to the point where he overachieves but also screws up his relationship. He goes to see his recently-made-ex-girlfriend Janine at her workplace - turns out she works in criminal forensics and is, along with the rest of the crew, done up in a Tyvek “bunny suit” with face mask, so her facial expressions are limited to what she can do with her blue eyes. The role isn’t credited, but it’s Cate Blanchett under that disguise. Obviously she’s actively “hiding” in that role rather than being out in the open, but she has a lot of screen time (comparatively) and her only-slightly-muffled voice and expressive eyes start narrowing down who it could be.
Are you fucking kidding me? Really? That’s Cate Blanchett?
Runs off to try to confirm.
Edit: Hoooooly shit. You were right!
Yeah, and per the Wiki article, she got the role because she was a fan of Shaun of the Dead. Apparently, so was Jim Broadbent, who got the awesome role of Frank Butterman.
I was watching the film and thinking ‘hmm, that voice sounds kinda familiar’ and later started puzzling over how yeah, it was funny to have a heart-to-heart with your ex when she’s all covered up in a protective suit, but it was still weird. Turns out it was a very clever cameo.
John Ratzenberger (later to become Cliff Claven on Cheers) is the rebel officer on Hoth who tells Leia that “the shield doors must be closed,” in The Empire Strikes Back.
And this is a big “duh,” because I’ve never watched the show, but I just realized from watching commercials that the lead actor on Breaking Bad is the goofy dad from Malcolm in the Middle!
I had teh same reaction the first time I saw Morse as a psychopath too. He was the nice, mild-mannered doctor guy.
He had a guest appearance on “Homicide: Life on the Street” as, I think, Balyiss’s brother or something. It was a little weird because while I don’t think the two actors look a whole lot like, they still seemed to have a family resemblance.
If you’ve ever seen Bryan Cranston doing an interview with Craig Ferguson, you’ll see that there’s a reason he was in a comedy show. He is not a serious man. 
Actually, it’s the reverse… I thought he was great on Malcolm, and I’m having trouble wrapping my head around him as the star of a gritty drama!