Johnny Galecki as Leonard Hofstadter: An experimental physicist with an IQ of 173, who received his Ph.D. when he was 24 years old. Leonard is a nerd who loves video games, comic books, and Dungeons & Dragons. Leonard is the straight man of the series, sharing an apartment in Pasadena, CA, with Sheldon Cooper. Leonard is smitten with his new neighbor Penny when they first meet, and they eventually marry.

Jim Parsons as Sheldon Cooper: Originally from Galveston, Texas, Sheldon was a child prodigy with an eidetic memory who began college at the age of eleven and earned a Ph.D. at age sixteen. He is a theoretical physicist researching quantum mechanics and string theory, and, despite his IQ of 187, he finds many routine aspects of social situations difficult to grasp. He is determined to have his own way, continually boasts of his intelligence, and has an extremely ritualized way of living. Despite these quirks, he begins a relationship with Amy Farrah Fowler, and they eventually marry.

Kaley Cuoco as Penny: An aspiring actress from Omaha, Nebraska. Penny moves in across the hall from Sheldon and Leonard. She waits tables and occasionally tends the bar at The Cheesecake Factory. After giving up hope of becoming a successful actress, Penny becomes a pharmaceutical sales representative. Penny becomes friends with Bernadette and Amy, and they often hang out in each other's apartments. Penny and Leonard form a relationship and eventually marry.

Simon Helberg as Howard Wolowitz: An aerospace engineer who got his master's degree at the Massachusetts Institute of Technology. Howard is Jewish and lived with his mother, Debbie (Carol Ann Susi). Unlike Sheldon, Leonard, Raj, Bernadette, and Amy, Howard does not hold a doctorate. He trains as an astronaut and goes into space as a payload specialist on the International Space Station. Howard initially fancies himself as a ladies man, but he later starts dating Bernadette, and they get engaged and married. Howard also has a tendency to waste money on toys and argues with Bernadette because of his oddly low income as an engineer and her high income as a pharmaceutical biochemist.

Kunal Nayyar as Rajesh Koothrappali: A particle astrophysicist originally from New Delhi, India. Initially, Raj had selective mutism, rendering him unable to talk to or be around women unless under the influence of alcohol. Raj also has very feminine tastes and often takes on a stereotypical female role in his friendship with Howard as well as in the group of four men. Raj later dates Lucy (Kate Micucci), who also suffers from social anxiety, but it eventually ends. He later speaks to Penny without alcohol, overcoming his selective mutism. He begins dating Emily Sweeney, and their relationship later becomes exclusive. In the series' final season, Raj has an on-again, off-again engagement with a fellow Indian, a hotel concierge named Anu (Rati Gupta). He also has a Yorkshire Terrier named Cinnamon.
These actors were first credited as guest stars and later promoted to main cast:

Sara Gilbert as Leslie Winkle (recurring season 1, starring season 2, guest seasons 3, 9): A physicist who works in the same lab as Leonard. In appearance, she is essentially Leonard's female counterpart and has conflicting scientific theories with Sheldon. Leslie has casual sex with Leonard and later Howard. Gilbert was promoted to a main cast member during the second season but resumed guest star status because producers could not come up with enough material for the character. Gilbert returned to The Big Bang Theory for its 200th episode.

Melissa Rauch as Bernadette Rostenkowski-Wolowitz (recurring season 3, starring seasons 4–12): A young woman who initially is a co-worker at The Cheesecake Factory with Penny to pay her way through graduate school, where she is studying microbiology. Bernadette is introduced to Howard by Penny; at first, they do not get along, apparently having nothing in common. They date and later get engaged and married. Although generally a sweet and good-natured person, Bernadette has a short fuse and can be vindictive and lash out when provoked.

Mayim Bialik as Amy Farrah Fowler (guest star season 3, starring seasons 4–12): A woman selected by an online dating site as Sheldon's perfect mate, Amy is from Glendale, CA. While she and Sheldon initially share social cluelessness, after befriending Penny and Bernadette, she eventually becomes more interested in social and romantic interaction. Her relationship with Sheldon slowly progresses to the point at which Sheldon considers her his girlfriend, and eventually, they get married. Amy believes she and Penny are best friends, a sentiment that Penny does not initially share. Amy has a Ph.D. in neurobiology.

Kevin Sussman as Stuart Bloom (recurring seasons 2–5, 7, starring seasons 6, 8–12): A mild-mannered, under-confident owner of a comic book store. A competent artist, Stuart is a graduate of the prestigious Rhode Island School of Design. Though he is socially awkward, he possesses slightly better social skills. Stuart implies he is in financial trouble and that the comic book store now also is his home. He is later invited to join the guys' group while Howard is in space. Stuart gets a new job caring for Howard's mother later. After Mrs. Wolowitz's death, Stuart continues to live in her home, along with Howard and Bernadette, until he finds a place of his own.

Laura Spencer as Emily Sweeney (recurring seasons 7–8, 10, starring season 9): A dermatologist at Huntington Hospital. Emily went to Harvard and delights in the macabre, and she states that she likes her job because she can cut things with knives. Prior to meeting Raj, Emily was set up on a blind date with Howard. After finding Emily's online dating profile, Raj has Amy contact her as his wingman instead. Their relationship becomes exclusive, but Raj later breaks up with Emily when he becomes infatuated with Claire (Alessandra Torresani), a bartender and children's author.
Given the list of the Big Bang Theory actress, select only the main cast.
Kaley Cuoco as Penny, Melissa Rauch as Bernadette Rostenkowski-Wolowitz, Mayim Bialik as Amy Farrah Fowler