Gaffney hosted two of her own television talk shows: Women Aloud! (which was shown on the Comedy Central network) and The Mo Show. She and friend Kathy Najimy wrote and starred in two off-Broadway shows, The Kathy and Mo Show: Parallel Lives and The Kathy and Mo Show: The Dark Side, both of which won Obie Awards. She also appeared in Seasons 4 and 5 of That '70s Show as Joanne Stupak, Bob Pinciotti's girlfriend, had a recurring role in Mad About You and guest starred in Friends. In addition, she appeared in the Kirstie Alley/Kirsten Dunst black comedy about beauty pageants, Drop Dead Gorgeous.
Gaffney appeared on the British television talk show The Full Wax starring Ruby Wax, in which she portrayed American correspondent Taffy Turner, in the recurring segment Taffy Turner: Inside America.
Gaffney went on to team up with Jennifer Saunders with a recurring role as Bo in the sitcom Absolutely Fabulous; in 2004, talks of a spin-off show began but nothing surfaced. She is co-host of the Women Aloud radio program on Greenstone Media.
Gaffney is from San Diego, California.