TV legend Bob Newhart will guest star as Professor Proton, the former host of Sheldon's (Jim Parsons) favorite science show. As it turns out, the science guru also happened to be a key player in the childhoods of both Sheldon and Leonard (Johnny Galecki).
Buzz Aldrin, the second man to walk on the moon, guest starred during season six, playing (naturally) an astronaut who enjoys sharing his accomplishments with anyone who will listen — including children on Halloween. Raj (Kunal Nayyar) shows newly returned astronaut Howard (Simon Helberg) a clip of Aldrin with the hope that his best friend might talk about his own trip to space a bit less.
Christine Baranski earned two Emmy nominations for guest actress in a comedy for playing Leonard's psychiatrist/neuroscientist — aka Sheldon's perfect woman (that is, before Amy). She has appeared multiple times on the CBS hit, including via Skype.
Star Trek's GeorgeTakei played himself in Howard's dream sequence — which also featured Battlestar Glactica's Katee Sackhoff. The dream helps Howard realize he still has feelings for his future bride, Bernadette (Melissa Rauch).
Kate Micucci of musical comedy duo Garfunkel & Oates (and Raising Hope) played Raj's first real love interest, Lucy, during season six. Despite both of their social hang-ups, the duo shared a sweet date at a library — during which they communicated via text message.
KateeSackhoff played one of the many women of Howard's dreams. During her first appearance (in season three), the duo shared an intimate bath — in the reformed horn dog's dream, naturally.
In keeping with Big Bang Theory's penchant for exploring the dream state, Star Trek's Leonard Nimoy guest starred with a voice role when a Spock action figure helped Sheldon deal with the guilt over breaking a valuable toy given to Leonard.
LeVar Burton has guest starred twice (so far), most recently returning for a special Star Trek-themed episode of web series "Sheldon Cooper Presents: Fun With Flags."
NASA astronaut Mike Massimino, right, played himself in a recurring role when Howard — aka "Fruit Loops" — journeyed to the great beyond. Massimino — a veteran of two space shuttle missions to service the Hubble Space Telescope — says that he was a fan of the show before booking the cameo gig and notes that Howard's cleverness would make him a "great person to fly with in space."
Sara Gilbert has appeared multiple times as Leslie Winkle, a fellow physicist at the university where Leonard, Sheldon, Howard and Raj work. While initially a love interest for Leonard, she eventually has a fling with Howard.
In an attempt to make up for missing Stan Lee's autograph signing, Penny (Kaley Cuoco) takes Sheldon to the comic book legend's house — uninvited. He ultimately winds up with an autograph — on a restraining order.
Sheldon's meeting with Stephen Hawking almost didn't happen after the uber-competitive geek spanked the theoretical physicist and cosmologist in a game of Words With Friends. "When people would ask us who a 'dream guest star' for the show would be, we would always joke and say Stephen Hawking — knowing that it was a long shot of astronomical proportions," executive producer Bill Prady said when the casting was announced. "In fact, we’re not exactly sure how we got him. It’s the kind of mystery that could only be understood by, say, a Stephen Hawking."
Apple's Steve Wozniak was quite impressed with the "virtual presence device" Sheldon created in an attempt to spare himself from the banalities of everyday socializing during a season four episode.
Terminator: The Sarah Connor Chronicles and Firefly alum Summer Glau had nowhere to run when the guys ran into one of their sci-fi favorites on a train ride to a Bay Area conference. While each attempted to hit on her, it was Howard who actually managed to get the (creepy) words out.
Wil Wheaton has appeared multiple times playing a heightened version of himself (read: He's a tool!) as a longtime nemesis for Sheldon. Before the duo nearly came to (drunken) blows, Wheaton helped break up Leonard and Penny, costing Sheldon and Raj a game of Mystic Warlords of Ka'ah. Sheldon's meemaw would approve of their new friendship.