She then began her career as a singer and actress. She played the lead in a new play at London's Royal Court Theatre, home of the new wave of playwrights of the 1950s such as John Osborne and Harold Pinter. This led to other stage performances such as the musical Valmouth in 1959, the play A Time to Laugh (with Robert Morley and Ruth Gordon) in 1962, and eventually to her show-stopping Julie in the Wendy Toye production of Show Boat at the Adelphi Theatre in London in 1971.
During this period she had two major recording successes. You'll Answer to Me reached the British Top 10 while Laine was 'prima donna' in the 1961 Edinburgh Festival production of Kurt Weill's opera/ballet The Seven Deadly Sins. In 1964 her Shakespeare and All that Jazz album with Dankworth received widespread critical acclaim, and to this day remains an important milestone in her identification with the more unusual aspects of a singer's repertoire.
1972 marked the start of Laine's international activities, with a successful first tour of Australia. Shortly afterwards, her career in the United States was launched with a concert at New York's Lincoln Center, followed in 1973 by the first of many Carnegie Hall appearances. Coast-to-coast tours of the U.S. and Canada soon followed, and with them a succession of record albums and television appearances The Muppet Show 1977. This led, after several nominations, to Cleo's first Grammy award, in recognition of the live recording of her 1983 Carnegie concert.
Other important recordings during that time were duet albums with Ray Charles (Porgy and Bess) and Mel Tormé (see Nothing Without You), as well as Arnold Schoenberg's Pierrot Lunaire which won Laine a classical Grammy nomination.
Laine's relationship with the musical theatre, started in Britain, continued in the United States with starring performances in Sondheim's A Little Night Music and The Merry Widow (Michigan Opera). In 1985 she originated the role of Princess Puffer in the Broadway hit musical The Mystery of Edwin Drood, for which she received a Tony nomination, and in 1989 she received the Los Angeles critics' acclaim for her portrayal of the Witch in Sondheim's Into the Woods.
In 1979 Laine was made an Officer (OBE) of the Order of the British Empire for services to music. In the 1997 New Year's Honours list, Laine's membership of the order was elevated to Dame Commander, and she was appointed Dame Cleo Laine DBE (the female equivalent of a knighthood).
In May 1992 Laine appeared with Frank Sinatra for a week of concerts at the Royal Albert Hall, London. She told a reporter in 2007: "I was very impressed with his singing, to me he sounded even better in those concerts than he did on the records. It was a real thrill to be part of his show."
On October 28, 2007, Laine turned 80. She marked her birthday with a series of special concerts in the UK, including an appearance with the John Dankworth sextet at Birmingham Town Hall on December 18. She said of her milestone birthday: " I don't think about being 80. What would be the point? I'm limping a bit because they've given me a new knee, but that's about the only difference. I don't want to start thinking about what I should or shouldn't be doing at my age. It's not right."