Etheridge has produced eight albums since signing her first major recording contract in 1987. Three of them have gone multi-platinum: Melissa Etheridge (1988), Yes I Am (1993) and Your Little Secret (1996). Two others went platinum and another gold.
She has won the Grammy award for Best Female Rock Vocal Performance twice in her career, for the song "Ain't It Heavy" in 1992 and "Come to My Window", in 1994.
She is a Bruce Springsteen fan, and she has covered his song "Thunder Road" during live shows.
On November 15, 2005, she appeared on the Tonight Show to perform her song "I Run For Life", which references her illness and her determination to overcome it. After her performance, Jay Leno told her, "Thanks for being a fighter, kiddo."