- Jennifer Aniston as Rachel Karen Green, a fashion enthusiast who starts working at the coffee shop Central Perk, but later moves into management at Bloomingdale's and later at Ralph Lauren.
- Courteney Cox Arquette as Monica E. Geller (later Geller-Bing), a chef who changes jobs often throughout the show, ending up as head chef at Javu.
- Lisa Kudrow as Phoebe Buffay (later Buffay-Hannigan), an eccentric masseuse and musician.
- Matt Le Blanc as Joseph (Joey) Francis Tribbiani Jr., a struggling actor who becomes famous for his role on Days Of Our Lives as Dr. Drake Ramoray.
- Matthew Perry as Chandler Muriel Bing, a sarcastic executive in statistical analysis and data reconfiguration for a large multi-national corporation. He is later a junior copywriter at an advertising agency and marries longtime friend Monica Geller.
- David Schwimmer as Ross Eustace Geller, Monica's older brother, a paleontologist working at a museum of Prehistoric 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 Doyle, 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 romantic comedies including Bruce Almighty, Along Came Polly, Rumor Has It and The Break Up. 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. She currently stars on the ABC sitcom Cougar Town. 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 and Analyze This. 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. He 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 and an episode of Scrubs titled "My Unicorn" as Murray. Matt LeBlanc took a leading role in Lost in Space and starred as the boyfriend of Alex (Lucy Liu) in Charlie's Angels. He also reprised his role as Joey Tribbiani in the show's spin off series, Joey. 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 a role which he reprised in 2008 for Madagascar 2.
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.