Manheim worked for a while as a sign language interpreter at hospitals. Her knowledge of sign language was utilized at times on The Practice, an episode of Law & Order and also for her role as a Child Behavioral Psychologist in the movie Mercury Rising. In 1998, Manheim collected an Emmy for her work on The Practice and exclaimed that "This is for all the fat girls!" She followed up on this statement with an autobiography entitled Wake Up, I'm Fat!. A one-woman show of the same name preceded the book.
In 2005, Manheim earned Golden Globe and Emmy nominations for her work in the acclaimed miniseries Elvis, and the following year she joined the cast of Ghost Whisperer. Her other television credits include Chicago Hope, Ally McBeal, Family Guy, Will & Grace, Boston Public, Two and a Half Men, The L Word, How I Met Your Mother and Hannah Montana.
In addition, Manheim has several film credits under her belt. These include Romy and Michele's High School Reunion, Happiness (which earned her and her co-stars an NBR Award for Best Ensemble), The Laramie Project, Scary Movie 3, Dark Water and An Unfinished Life.