Born in New York City to Martin Balsam and Joyce Van Patten, Balsam made her television debut in Alexander: The Other Side of Dawn in 1977 and in 1979, Survival of Dana. She appeared in multiple episodes of Happy Days, Taxi, thirtysomething, Murder, She Wrote, Almost Perfect, Archie Bunker´s Place, L.A. Doctors, and K Street. In more recent years she has had recurring roles as Anthony LaPaglia's estranged wife on Without a Trace and Mona Sterling on Mad Men opposite her husband, John Slattery. She also acted in at least one episode of Family Ties opposite Michael J. Fox.

Balsam made her Broadway debut in the 1992 Neil Simon play Jake's Women and won the Theatre World Award for her performance.

Balsam's screen credits include Mass Appeal, Little Manhattan, All the King's Men, and The Wackness.

Balsam was married to George Clooney from 1989 to 1993.