Cosmologist Stephen Hawking made a short guest appearance in the fifth-season episode; in the eighth season, Hawking video conferences with Sheldon and Leonard, and makes another appearance in the 200th episode. In the fifth and sixth seasons, NASA astronaut Michael J. Massimino played himself multiple times in the role of Howard's fellow astronaut. Bill Nye appeared in the seventh and twelfth seasons.
In November 2016, it was reported that CBS was in negotiations to create a spin-off of The Big Bang Theory centered on Sheldon as a young boy. The prequel series, described as "a Malcolm in the Middle-esque single-camera family comedy" would be executive-produced by Lorre and Molaro, with Prady expected to be involved in some capacity, and intended to air in the 2017–18 season alongside The Big Bang Theory. The initial idea for the series came from Parsons, who passed it along to The Big Bang Theory producers. In early March 2017, Iain Armitage was cast as the younger Sheldon, as well as Zoe Perry as his mother, Mary Cooper. Perry is the real-life daughter of Laurie Metcalf, who portrays Mary Cooper on The Big Bang Theory.
After Sheldon reminds the guys about the time they mined Bitcoin without him, the guys go on a quest to find their suddenly valuable missing cryptocurrency. They realize the currency is on a laptop which Leonard gave to Penny when they dating, which she then gave to her ex-boyfriend Zack. After Leonard and Penny go to Zack's apartment, he shows them a seven-year-old video that Penny recorded on the laptop soon after she broke up with Leonard. Leonard is touched by the video which shows a drunk Penny lamenting the break-up of her relationship with him.