Clayton began her recording career in 1962 at the age of fourteen, singing "Who Can I Count On? (When I Can't Count On You)" as a duet with Bobby Darin on his album "You're The Reason I'm Living". A year later, she recorded the first version of "The Shoop Shoop Song (It's in His Kiss)", although it was Betty Everett's version of the same year that reached the top 10 in the Billboard Hot 100. Her early career included performances with artists including Ray Charles (as one of The Raelettes), Pearl Bailey, Phil Ochs, and Burt Bacharach. (She is often credited as having recorded with Elvis Presley but her name does not appear in Elvis sessionographies.)In 1971 she co-wrote the song "Sho' Nuff", which is about her mother. She contributed vocals to Donald Cammell and Nicolas Roeg's 1968 film Performance.
Clayton also sang backup on several tracks from Neil Young's debut album Neil Young, originally released in 1968.
She is best known for her 1969 performance in a duet with Mick Jagger on the Rolling Stones song "Gimme Shelter". (Originally, the Stones had intended to have Bonnie Bramlett sing, but Bramlett was not available, possibly because of illness.) Clayton also sang backing vocals on Lynyrd Skynyrd's "Sweet Home Alabama".Also, early in her career, Clayton sang backup vocals for Tom Jones, Joe Cocker ("Feelin' Alright") and Carole King. She also originated the role of the Acid Queen in the original 1972 London production of The Who's Tommy. More recently, Clayton has provided background vocals for Sparta's latest album Threes on the songs "Atlas" and "Translation". As an actress, she co-starred with Ally Sheedy in the 1987 film Maid to Order, and played Verna Dee Jordan in the final season of Cagney & Lacey.