Cates was born Phoebe Belle Katz in New York City; her father is director Joseph Cates and her uncle is Gilbert Cates, also a director. Her father is of Jewish heritage; her maternal grandfather was a Chinese Filipino and her maternal grandmother was a Russian Jew. Cates attended the Professional Children's School. She followed in the steps of her father and uncle in changing her surname for professional reasons.

She achieved icon status in the early 1980s for her role in the teen comedy Fast Times at Ridgemont High, in which she stripped off her bikini top in a slow-motion fantasy sequence. She was considered one of the most beautiful actresses in the early 80's. Harper's Bazaar magazine, in 1984, included her in their list of America's 10 Most Beautiful Women.

That same year, in the romance film Paradise, and in contrast to the coyness of Brooke Shields in the similarly themed and more popular The Blue Lagoon, Cates appeared nude, although she was said to have used a body double in some of the close-ups. In a People magazine article, Cates said she had expressed reservations about this situation to her father, who advised her to play it in whatever way she felt was artistically honest.

Her later roles were more modest and largely oriented toward younger audiences, who remember her best as the female lead in the two Gremlins films. Her face made the covers of teen magazines such as Seventeen, Tiger Beat, Teen Beat and others.

In 1989, she married actor Kevin Kline, whom she had originally met while auditioning for the part that Meg Tilly ultimately won in The Big Chill. In 1991, she was slated to be in Father of the Bride, but dropped out due to pregnancy. In 1996, she narrated the award-winning documentary short, The Flame, a film about the nonprofit world hunger organization Heifer International.

Kline and Cates make their home in New York City and have three children, Owen, born in 1991 (who recently received rave reviews for his performance in The Squid and the Whale), Greta, born in 1994, and Autumn Belle, born in December 2005. They all (with the exception of Autumn) appeared in Cates' most recent film, The Anniversary Party (2001). The film was an ensemble comedy written and directed by Scottish actor Alan Cumming and Cates' real-life best friend of the past 25 years, Fast Times at Ridgemont High co-star Jennifer Jason Leigh, and in it Cates played, fittingly enough, a Hollywood actress who has retired from acting to be a full-time mother.

In 2005, Cates opened her own gift store/boutique emporium called Blue Tree on New York's Madison Avenue.

Pop/Rock band Fenix TX wrote a song entitled "Phoebe Cates" on their album called Lechuza. The song contains lyrics such as "I'm looking for a fast time, Watching out for bright lights, Send me off to private school, When I'm with you it's paradise." This is a play on words containing four of her movie titles. Another line goes: "Wasting time... going blind.... I've been in love since the day I saw Fast Times, It's on a permanent rewind and can you guess my favorite part?, I used to like tossing off to her pool scene, Now I'm kissing TV screens..."