Rhea has said that her true training came from her first gigs at the comedy club Catch A Rising Star. Performing around New York City, she quickly gained a reputation, and a name in the city's competitive comedy scene. These performances were augmented with appearances on MTV's Half-Hour Comedy Hour, Comic Strip Live and Caroline's Comedy Hour. She decided to move to Los Angeles for a career in Hollywood, debuting in NBC television series Pride & Joy co-starring with Jeremy Piven. She gained most fame for her role as "Aunt Hilda" on the ABC and The WB's Sabrina, the Teenage Witch, as well as being a regular on the latest incarnation of Hollywood Squares, with Tom Bergeron and Whoopi Goldberg (in the center square).

In 2002, Rhea landed her own syndicated daytime talk show, The Caroline Rhea Show. Rosie O'Donnell had hand-picked Rhea as her replacement. Rhea next went on to host the autumn series, The Biggest Loser on NBC, which was the first weight loss reality show in whi