- Jennifer Aniston as Rachel Green, a waitress for Central Perk who later gets a career in fashion management at Bloomingdale's and later at Ralph Lauren.
- Courteney Cox Arquette as Monica Geller-Bing, a neurotic chef who works at several restaurants throughout the series.
- Lisa Kudrow as Phoebe Buffay, an eccentric masseuse and musician.
- Matt LeBlanc as Joey Tribbiani, a womanizer and struggling actor who becomes famous for his role on Days Of Our Lives as Dr. Drake Ramoray.
- Matthew Perry as Chandler Bing, an executive in statistical analysis and data reconfiguration for a large multi-national corporation. He is later a junior copywriter at an advertising agency.
- David Schwimmer as Ross Geller, Monica's older brother, a paleontologist working at a museum of Natural History and later a professor of paleontology at New York University.
Two of the series' stars, Matthew Perry and Jennifer Aniston, had already appeared in several unsuccessful sitcom pilots. Another, Lisa Kudrow, was also familiar with working on sitcoms, having played Ursula Buffay on Mad About You. (In an interesting twist, it was revealed in Friends that Phoebe was Ursula's twin sister.) Kudrow was cast in the pilot of Frasier in the role of Roz, but the part was later re-cast with Peri Gilpin in the role.  Courteney Cox was already an accomplished TV and film actress when she was cast in Friends, having appeared in the likes of Ace Ventura: Pet Detective and with several minor roles on sitcoms such as Seinfeld and Family Ties. The character of Ross was written with David Schwimmer in mind; having auditioned for Crane and Kauffman in the past, Schwimmer was said to have a memorable voice and was most known for his Broadway work. Matt LeBlanc appeared as Vinnie Verducci in Married... with Children in the early 1990s and starred in that sitcom's short-lived spin-off, Top of the Heap, as well as in the unrelated Vinnie & Bobby, but before that had mainly been focusing on advertising and modeling work when he was cast as Joey Tribbiani.
During the show's run, the cast all achieved household name celebrity status, and all pursued careers in the movies, with varied success. Aniston's movie career is predominantly populated with light rom-coms. Cox made several lightweight films and achieved her greatest success with the Scream series, followed by the critically acclaimed TV series, Dirt, that portrayed her as a ruthless editor of a two-bit tabloid magazine. Kudrow fared best in low budget indie films, most notably The Opposite of Sex, and also films like the comedy hit Romy and Michelle's High School Reunion. Most recently Kudrow played a main character alongside Hilary Swank in 2007's P.S. I Love You. Perry co-starred in the Canadian mafia comedy The Whole Nine Yards and its sequel The Whole Ten Yards along with Bruce Willis, who had also made guest appearances on the show. Perry also starred as the title character in The Ron Clark Story, and has since co-starred in TV drama Studio 60 on the Sunset Strip. Matt LeBlanc took a leading role in Lost in Space. In 2001, Schwimmer co-starred as Capt. Herbert Sobel in the 2001 TV mini-series Band of Brothers. In 2005, Schwimmer starred as the voice for the giraffe Melman in the movie Madagascar. In 2006 he co-starred in black comedy Big Nothing alongside Alice Eve and Simon Pegg. In 2007, Schwimmer directed British comedy Run, Fat Boy, Run also starring Pegg, and Hank Azaria, another star who has made guest appearances on Friends. In November 2008 Schwimmer will reprise his role as Melman the giraffe in Madagascar 2. LeBlanc continued his role as Joey Tribbiani for the main character in the spin-off sitcom Joey.
Behind the scenes, the show was known for its unusually cohesive and unified cast. The six main actors made deliberate efforts, from early on, to keep the show's ensemble format and not allow one member to dominate; notably for a show of its length, the six principals each appeared in every episode of the run. This included requesting that all actors on the show be nominated either for the same category of award (Supporting Actor until 2001, then Lead Actor from 2002 onwards) or not at all, and entering collective instead of individual salary negotiations. The actors became such close friends that one guest star, Tom Selleck, reported sometimes feeling left out. The cast remained good friends after the show's run, most notably Cox and Aniston, with Aniston being godmother to Cox and David Arquette's daughter, Coco.