David Schwimmer portrays Ross Geller, Monica Geller's older brother, a paleontologist working at the Museum of Natural History, and later a tenured professor of paleontology at New York University. Ross is a sweet-natured man of good humor, although he is often clumsy and socially awkward. Ross is involved in an on-again-off-again relationship with Rachel throughout the series. He has three failed marriages during the series: Carol Willick, a lesbian who is also the mother of his son, Ben; Emily Waltham, who divorces Ross after he accidentally says Rachel's name instead of hers during their wedding vows; and Rachel, as the two drunkenly marry in Las Vegas. His failed love life is potentially due to his paranoia and jealousy in relationships, and his divorces become a running joke within the series. Following a one-night stand, he and Rachel have a daughter, Emma, by the end of season eight. They finally confess that they are still in love with each other in the series finale.

Jennifer Aniston portrays Rachel Green, a fashion enthusiast and Monica Geller's best friend from childhood. Rachel first moves in with Monica in season one after nearly marrying Barry Farber, whom she realizes she does not love. Rachel and Ross Geller are later involved in an on-again-off-again relationship throughout the series. Rachel dates other men during the series, such as an Italian neighbor, Paolo, in season one; Joshua Bergin, a client from Bloomingdale's, in season four; Tag Jones, her assistant, in season seven; and Joey Tribbiani in season ten. Rachel’s first job is as a waitress at the coffeehouse Central Perk, but she later becomes an assistant buyer at Bloomingdale's in season three, and a buyer at Ralph Lauren in season five. Rachel and Ross have a daughter named Emma in "The One Where Rachel Has a Baby, Part Two" at the end of season eight. In the final episode of the series, Ross and Rachel finally confess their love for each other, and Rachel gives up a job in Paris to be with him.

Matthew Perry portrays Chandler Bing, an executive in statistical analysis and data reconfiguration for a large, multinational corporation. Chandler hates this job, although it pays well. He attempts to quit during season one, but is lured back with a new office and a pay raise. He eventually quits this job in season nine due to a transfer to Tulsa. He becomes a junior copywriter at an advertising agency later that season. Chandler has a peculiar family history being the son of an erotic novelist mother and a gay, cross-dressing Las Vegas star father. Chandler is known for his sarcastic sense of humor and bad luck in relationships Chan.dler marries Monica in season seven, and they adopt twins at the end of the series. Before his relationship with Monica, Chandler dated Janice Hosenstein in season one and subsequently broke up with her many times. Matthew Perry has expressed his similarities to the character, such as his need to break an awkward silence with a joke and difficulties with women when first joining the show.

Courteney Cox portrays Monica Geller, the mother hen of the group and a chef, known for her perfectionist, bossy, competitive, and obsessive-compulsive nature. Monica is often jokingly teased by the others for having been extremely overweight as a child, especially by her brother Ross. Monica works as a chef in various restaurants throughout the show. Monica’s first serious relationship is with long-time family friend Richard Burke, who is twenty-one years her senior. The couple maintains a strong relationship for some time, until Richard expresses that he does not want to have children, much to Monica’s dismay. Monica and Chandler Bing later start a relationship after spending a night with each other in London in the season four finale, leading to their marriage in season seven and adoption of twins at the end of the series.

Matt LeBlanc portrays Joey Tribbiani, a struggling actor and food lover who becomes famous for his role on soap opera Days of Our Lives as Dr. Drake Ramoray. Joey is a simple-minded womanizer with many short-term girlfriends. Despite his womanizing, Joey is innocent, caring, and well-intentioned. Joey often uses the catchphrase pick-up line "How you doin'?" in his attempts to win over most of the women he meets. Joey rooms with his best friend Chandler for years, and later with Rachel. He falls in love with Rachel in season eight, but Rachel politely tells Joey that she does not share his feelings. They eventually date briefly in season ten, but after realizing it will not work due to their friendship and, more importantly, Rachel's complicated relationship with Ross, they return to being friends.

Lisa Kudrow portrays Phoebe Buffay, an eccentric masseuse and self-taught musician. As a child, Phoebe lived in uptown New York with her mother, until she committed suicide and Phoebe took to the streets. Phoebe is ditsy but street smart. She writes and sings her own quirky songs, accompanying herself on the guitar. She has an "evil" identical twin named Ursula, who shares Phoebe’s quirkiness, but, unlike Phoebe, seems to be selfish and uncaring. Phoebe is childlike and innocent in disposition. She tends to use her past misfortunes such as her mother’s suicide as sympathy ploys – or rather, to mock others' self-indulgent self-pity. Phoebe has three serious relationships over the show's run: David, a scientist, in season one, whom she breaks up with when he moves to Minsk on a research grant; Gary, a police officer whose badge she finds, in season five; and an on-and-off relationship with Mike Hannigan in seasons nine and ten. In season nine, Phoebe and Mike break up due to his desire not to marry. David returns from Minsk, leading to the two getting back together, but she eventually rejects him for Mike when both of them propose to her. Phoebe and Mike marry in season ten.