Reese moved to New York in 1953 to be a singer with the Erskine Hawkins Orchestra and obtained a recording contract. In 1957, her hit single "And That Reminds Me" earned Reese her first berth (of 20 total) on "The Ed Sullivan Show" and awards as Most Promising Singer from Billboard, Cashbox and Variety. The next year, she signed with RCA and released "Don't You Know", which became her biggest-selling single, and which she sang in her screen debut as herself in "Let's Rock" (1958). (The song was also prominently featured in the soundtrack of 1993's film "A Bronx Tale".)

Reese parlayed her fame as a singer into her own syndicated talk-variety series, which ran from 1969-70, and made her dramatic TV debut in a 1970 episode of "The Bold Ones". In 1973, she also made her TV-movie debut playing Michael Evans' mother in "The Voyage of the Yes" and had a small role in the miniseries "Roots: The Next Generations" (1979). In 1976, she joined the cast of the NBC sitcom "Chico and the Man", as Jack Alberston's landlady, which she played for two seasons. This established her as a comic actress. Reese subsequently co-starred as a judge on "It Takes Two" (ABC, 1982-83) and as the meddlesome Aunt Rachel in "Charlie & Co." (CBS, 1986). She got her chance to star in "The Royal Family" (CBS, 1991-92), playing Redd Foxx's wife, but Foxx's untimely death was also the eventual death knell for the series. But Reese's association with Eddie Murphy, who was executive producer of the series, was ongoing. Although she had a part in the low-budget 1975 feature "Psychic Killer", she made her first feature film appearance in a studio film with "Harlem Nights" (1989). Murphy not only directed the film, but as star, he got to deck Reese's obnoxious character to the delight of the audience. Reese also starred in "The Kid Who Loved Christmas", a syndicated 1990 TV-movie from Murphy's company. Reese found herself the darling of young black comics. Martin Lawrence cast her as his mother in "The Thin Line Between Love and Hate", his 1996 directorial debut.

Reese moved from comedy to drama in 1994 when she starred in "Touched By an Angel" (CBS), in which she was Tess, the older and wiser guiding spirit to novice Roma Downey. The anthology series was a surprise hit; its message that the Almighty exists and has a plan for the average person tied in with Reese's concurrent career as a minister connected to the Universal Foundation for Better Living. She heads her own church in L.A.