These characters started out as recurring characters, and were later promoted to main cast. These characters do not appear in all episodes, and are only credited in episodes in which they appear.
Dr. Leslie Winkle (Sara Gilbert) (appeared in eight episodes total, four credited as main cast) is an optical physicist who works in the same lab as Leonard. In appearance, she is essentially Leonard's female counterpart, equipped with the black framed glasses and sweat jackets. She is Sheldon's arch-enemy, due to their conflicting scientific theories. Though they both consider each other to be intellectually inferior, Leslie is much wittier than Sheldon, regularly calling him "dumbass" and besting him in their repartée. Leslie has had casual sex relationships with Leonard and later Howard. Leslie stopped appearing in the series after the finale of season 3, when Leonard, being desperate for physical contact, asked to get back on with Leslie. She closed the door in his face and did not appear.
Dr. Bernadette Maryann Rostenkowski (Melissa Rauch): (appeared in 30 episodes total, 25 credited as main cast) is a waitress and co-worker of Penny at the Cheesecake Factory, which pays the way for her graduate studies in microbiology. A recurring joke on the series is reference to Bernadette handling infectious biological specimens before preparing food or making physical contact with people, which eventually results in her and her entire research team spending New Year's Eve 2010 in quarantine. She went to a Catholic school and cannot lie very well because, according to her, the teachers "whip the lying out of you". Bernadette is introduced to Howard by Penny. At first she and Howard do not get along, as they appear to have nothing in common. When they find out that they both have overbearing mothers, they feel a connection. Subsequently, Howard realizes Bernadette presents a real opportunity to develop a lasting relationship, and, in an impulsive manner, he proposes to her. Although Bernadette rejects his offer, they remain a couple for a time after Howard sings a heartfelt song for her at the Cheesecake Factory, which Penny finds quite embarrassing but Bernadette finds romantic. Eventually they break up after she discovers Howard, via his World of Warcraft character, having sex with another online character. Bernadette and Howard reconcile and resume their relationship, ultimately culminating in their engagement in the season 4 episode, "The Herb Garden Germination". In "The Roommate Transmogrification", she finally obtains her Doctorate and is subsequently hired by a pharmaceutical company that promises her "a buttload of money". This makes Howard jealous, especially after the rest of his friends taunt him about his lack of a Doctorate. It eventually leads to them having an argument after she purchases a Rolex watch for Howard, which he interprets as her "rubbing in" the fact that she now earns more than him. The already soured relationship turned worse when Raj admitted out loud that he fantasizes about Bernadette and writes love poems about her, causing Howard to now distrust Bernadette. As soon as she found out, Bernadette stormed over to Raj's apartment and severely scolded him.
Dr. Amy Farrah Fowler (Dr. Mayim Bialik) (appeared in 26 episodes total, 21 credited as main cast) is a neurobiologist (which corresponds to Bialik's real-life Ph.D.). Raj and Howard met her on an online dating site after secretly setting up an account using Sheldon's name and information. The site matches her to Sheldon, and the two share many similar traits. Once she and Sheldon meet, she becomes, as Sheldon puts it, a girl who is his friend, but not his "girlfriend". They briefly ended their friendship when they got into an argument over whose field of study was superior. The two initially communicate only by text message and occasionally via webcam, though she gradually began hanging out with the group in person through the fourth season. After they announce their intention to have a child, Penny ends up chaperoning their first date together since neither of them drive. Besides being friends with Sheldon, Amy also injects herself into Penny's life and attempts to bond with Penny and Bernadette (even considering Penny to be her best friend, or "bestie"), but frequently makes them uncomfortable by misinterpreting "girl talk" to mean openly discussing topics such as female anatomy and feminine hygiene. While she has clearly indicated a desire to experience physical intimacy with Sheldon (a sentiment Sheldon doesn't share), she also often makes comments about Penny indicating a physical attraction to her. However, as shown in "The Shiny Trinket Maneuver", Amy has a very girly side, and falls in love with a tiara (an apology present from Sheldon). She's shown to have something of an arrogant side in "The Pulled Groin Extrapolation", where she's convinced that Leonard has fallen for her after he accompanies her to a friend's wedding, even though he has no such feelings. In "The Isolation Permutation", Amy reveals that she had very few friends from pre-school through grad-school. In "The Benefactor Factor", it is revealed that she is technically engaged to Saudi Arabian Prince Faisal who resides in Riyadh, who is the source of much of her lab's funding. Amy can also play the harp. In Season Five, Amy made Sheldon jealous by going on a date with comic book store owner Stuart, causing Sheldon to solidify their relationship as boyfriend/girlfriend. Sheldon then insisted that Amy sign a 31-page "Relationship Agreement" which is more beneficial to Sheldon. Amy Fowler has a Ph.D. in neurobiology, with a research focus on addiction in primates and invertebrates. She has successfully taught a monkey to smoke cigarettes, and has nearly gotten a starfish hooked on cocaine. The actress portraying Amy Farrah Fowler, Mayim Bialik, was mentioned by Raj ("the girl who played TV's Blossom") in episode 1.13, "The Bat Jar Conjecture", as a possible substitute for Sheldon on their Physics Bowl team.