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In one episode, Kaley Cuoco's character Penny is talking about an upcoming play and says, "This could be my only chance to play Anne Frank." In 8 Simple Rules, Kaley Cuoco's character Bridget was Anne Frank in her school play.
Penny later got a commercial gig that showed her riding horses. Kaley is an avid rider, and in fact broke her leg the previous season after she fell and the horse trotted over it.
Courtney Ford showed up as a geeky girl and made a reference to Superman. Ford is not only quite geeky herself, but is married to Brandon Routh of Superman Returns.
In an early episode, the boys consider recruiting "TV's Blossom" (Mayim Bialik) to their Physics Bowl team, as Raj has heard she has a Ph.D. in "neuroscience or something." Dr. Bialik does, in fact, have a Ph.D. in neuroscience, and later appeared on the show as Amy Farrah Fowler, a neurobiologist. After the Bialik suggestion gets shot down, he then suggests "that girl from The Wonder Years" and Danica McKeller later had a guest spot as Abby, one of the girls Sheldon meets and are impressed by his Green Lantern's limited edition Lantern.
Sara Gilbert appears throughout the series as Leslie Winkle, a sort of friend-with-benefits for Leonard. She and Johnny Galecki (Leonard) played supporting roles on Roseanne, in which they played a couple (eventually married) with essentially the same dynamics of passive guy/sarcastic dominating girl.
Sheldon makes reference to the theme to Teenage Mutant Ninja Turtles 1987 as being his favorite tv theme song. A lesser known fact of creator Chuck Lorre is that he used to be a music composer for kids shows before he got into sitcom writing, and one of his songs actually was that theme.
Actor-Shared Background: Raj was originally going to be an American-born Indian until Nayyar was cast, with him being much more Indian (actually raised in India) than planned. Jim Parsons is also from Texas like Sheldon is and although Parsons' accent doesn't come in very often with Sheldon, Sheldon's mother and sister have very thick drawls. Mayim Bialik, who plays neurobiologist Amy Farrah Fowler, has a PhD in neuroscience.
In Australia, the Nine Network has this feeling toward the series; it usurped Two and a Half Men as their go-to filler whenever there's a gap in the timetable, and between the main Nine channel and its spillover GO!, it's shown with incredible frequency.
It's in constant looping on the UK's "E4" channel as well. Not just one loop either, but two. The loops are deliberately out of synch so that one might be in Season 3, while the other is still in Season 1.
In the U.S. it's replaced The Office (US) as TBS's Tuesday night marathon show.
Creator Thumbprint: In "The Gothowitz [...]", Leonard, Sheldon, and a confused Penny are watching the fictional anime "Ochikurru: Demon Samurai". In series creator Chuck Lorre's other most famous show, Two and a Half Men, Charlie was once hired to write the theme song for the show when it was being developed.
Defictionalization: The gang plays a card game called "Mystic Warlords of Ka'a". An actual card release is planned, and the game can currently be played on Facebook.
Fake Nationality: Averted with Raj but not with his parents. British-Israeli Brian George and British actress Alice Amter play Indians. Raj's sister Priya (Aarti Mann) was born and raised in Pittsburgh.
Hey, it's Christine Baranski, who played an Expy of Patsy Stone on Cybill. As Leonard's mom. And in 3rd Rock from the Sun - she was a love interest for unworldly eccentric physics professor Dick Solomon...
Hey, it's Sara Rue. In one of the same episodes she appeared in, Penny is trying to make Leonard jealous by kissing on Keith Dudemeister
The HR lady is played by the chick that voices both Huey and Riley Freeman in the animated series The Boondocks.
In Memoriam: The ninth episode in the series, The Septum Deviation, incorporates homage to Carol Ann Susi (voice of Debbie Wolowitz) who sadly died during the screening of the new season. See here.
Life Imitates Art: Johnny Galecki (Leonard) and Kaley Cuoco (Penny) actually did date for two years; they did so in secret and only revealed it after they had separated.
Milestone Celebration: The 100th episode, "The Recombination Hypothesis", in which Leonard decides he wants to get back together with Penny.
One of Us: Nobel Laureate George Smoot made an appearance on the show after expressing his love of the show to the producers, with the episode actually written for him.
Melissa Rauch said she was a fan of the show before she was cast as Bernadette. On the other hand, Mayim Bialik admitted she didn't watch the show before she auditioned.
Real-Life Relative: In the 2013 Valentines Day episode Kaley Cuoco's sister Briana played an ex-friend of Penny's named Gretchen with whom an ex-boyfriend of cheated on her with.
Romance on the Set: Johnny Galecki and Kaley Cuoco — yes, Leonard and Penny. However, they kept it secret until after they broke up... which was around the time their characters first got together. (They kept it secret because of the work environment and remain friends.)
Scully Box: As is normal for exceptionally small actresses being paired against taller actors, Bernadette is almost never seen without some sort of lift in her shoes.
The Red Stapler: When Sheldon wears a T-shirt, people want it. The same goes for items like the periodic table shower curtain or the Cylon toaster.
Those Two Guys: Johnny Galecki and Sara Gilbert pairing up for a while in Season 2; they played love interests and eventually husband and wife on Roseanne and dated in real-life (Gilbert admitted Galecki was her Last Het Romance).
A noted aversion. The cast has said that they know almost as much about the nerd culture references as they do the technobabble — AKA, nothing. Going off-script would be suicide.
Melissa Rauch said that her vocal pitch for Bernadette was based on her mother's voice and thought it would fit the character, though she decided not to push it by including a New Jersey accent.
In "The Boyfriend Complexity" Sheldon angrily tosses a large stack of loose papers in the air in frustration over hard work that was ultimately pointless. As the pages floated to the ground one managed to perch perfectly on his shoulder, and Parsons managed to stay in character long enough for that shot to remain in the final cut (trying to stare in anger at Galecki, he wasn't able to say his next lines without cracking up).
The, somewhat infamous, spanking scene with Sheldon and Amy was not originally going to be on camera. The episode was supposed to have a Running Gag of hearing Sheldon taking care of Amy and having some Innocent Innuendo implied coming from the bathroom as the audience listens from the main room. As filming for the episode began the joke wasn't working the way they wanted it to and so they ended up actually showing the scene in front of the audience. The other cast members commented that they would emerge from their dressing rooms and were shocked.
One episode featured the guys telling Penny about General Zod when Kunal ad-libbed "Good story," despite the fact that Raj can't talk to women. He immediately covered his mouth in shock, keeping the moment (roughly) in-character.
What Could Have Been: The original (unaired) pilot for the series was quite different; Sheldon and Leonard were the only carry-overs. The Penny role was a girl named Katie (played by Amanda Walsh), a hard drinking party girl who was a new roommate and the guys would help her break out of her shell. Leonard and Sheldon's only friend was a female co-worker named Gilda (Iris Bahr) who had a crush on Leonard, felt threatened by Katie's presence, and had once slept with Sheldon (who wasn't asexual). Lastly, the set design was much darker with them living in a very run-down building. Test audiences hated Katie but really liked Leonard and Sheldon, which gave them a rare opportunity to revise the concept with a second pilot. Many of the same jokes and lines of dialogue were reused in the first season, especially the introduction to the guys' white boards and their argument over the number of dimensions used.
Kaley Cuoco was considered for the role of Katie, but was busy with other things at the time and it was felt the cynical character wasn't a good fit for her. When creating Penny they actually had Kaley in mind to reflect a much more bubbly and warm individual, to avoid the trappings of the Katie disaster.
Bill Prady said that Kevin Sussman (who portrays Stuart) was a runner-up for the role of Howard.
The show originated under two different concepts, one being Bill Prady's experience working with a group of eccentric computer programmers back in the 80's and another under the idea of a young woman entering the real world of finding a job and making new friends. Realizing the key to both shows was on the secondary cast providing some contrast they decided on their own X Meets Y and combined them. After that they decided to move the genius nerds away from computers and make them scientists instead, pushing them outside a comfort zone.
The pilot had Sheldon & Leonard taking in a homeless woman who had just gone through a big breakup with the man she was living with, and deciding to reform her. Had the show continued in that direction, she would have gone along with it mostly because she had nothing better going on in her life, and would have been Leonard's and/or Sheldon's love interest.
Word of Saint Paul: The conflict in "The Love Car Displacement" centered around Howard feeling inadequate after meeting Bernadette's ex-boyfriend Glenn, played by former basketball player Rick Fox. Humorously, Fox commented that, in his mind, Glenn was driven crazy seeing Bernadette with Howard and caused a lot of self-doubt along the lines of, "How am I losing to this guy?" The character was physically in one early scene and had a couple of offscreen lines towards the end, so there is really nothing to support or contradict it.