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The star of the show is Jim Parsons as Texas native Sheldon Cooper (B.S., M.S., M.A. Ph.D., Sc.D), a theoretical physicist at Caltech. Sheldon has an IQ of 187 as well as an eidetic memory and repeatedly points out his superiority over the rest of the group. He lacks, however, various social skills, such as empathy or the ability to understand sarcasm. Sheldon has a twin sister, Missy, and an older brother, George.

Johnny Galecki stars as Leonard Hofstadter, an experimental physicist at Caltech University and roommate to Sheldon Cooper. Leonard often struggles to overcome his geeky awkwardness and insecurities which, over the course of the series, he continually improves. His main love interest is his neighbor, Penny, though due to the on-off nature of their relationship in the earlier seasons of the show, Leonard has dated a few women, including Raj's sister Priya.

The show starts with Kaley Cuoco as Penny moving in across the hall from Sheldon and Leonard, who takes an instant liking to her. Contrary to the group of friends, Penny has no academic career but pays her bills with a waitressing job at The Cheesecake Factory while waiting for her big break in Hollywood. She struggles to find work as an actress and eventually takes on a full-time position as a pharmaceutical sales rep with her friend Bernadette's company. Penny's last name is never revealed but can be assumed to be Hofstadter after her wedding to Leonard.

Howard Wolowitz, played by Simon Helberg, is an aerospace engineer and (briefly) astronaut. As the only member of the group aside from Penny without a PhD, Howard is often the source of Sheldon's mocking. In Season 3, Howard begins dating Penny's friend Bernadette and later marries her in Season 5. Howard builds technology for the International Space Station and is subsequently asked by NASA to join an expedition to the ISS as a payload specialist.

Kunal Nayyar portrays Indian astrophysicist Rajesh Koothrappali, born to wealthy parents but often claims to come from a humble background. His most significant flaw is the inability to talk to women, which he eventually overcomes with the aid of alcohol, leading to various awkward situations. He has a very effeminate side, illustrated by him often pointing out that he likes very unmanly things such as Sex and the City, Sandra Bullock movies or Hannah Montana.

At the end of Season 3, Mayim Bialik is introduced as Amy Farrah Fowler, a match to Sheldon's online dating profile set up by Howard and Raj. Initially, Amy dates Sheldon because she promised her mother to date once a year but soon grows very affectionate towards him. Later, Amy also befriends the girls (especially Penny). She is the most awkward of them and has often dreamed of being part of "the in crowd" like she now claims to be as Penny's best friend.

Melissa Rauch stars as Bernadette Rostenkowski, a microbiologist with a former part-time job at The Cheesecake Factory. She is introduced to Howard via Penny, after Leonard requests her to set up Howard on a blind date with one of her friends. The two initially bond over their overbearing mothers and eventually begin a relationship and marry at the end of Season 5. Bernadette is often compared to Howard's mother when she yells and generally speaks in a high-pitched voice that Melissa Rauch uses specifically for the role.