An accomplished stage actress, Brooke Smith has acted in many feature films, including Daniel Minahan's Series 7, Jonathan Demme's The Silence of the Lambs, Louis Malle's Vanya on 42nd Street (for which she received an IFP Spirit Award nomination for Best Supporting Actress), Robert Altman's Kansas City, Henry Jaglom's Last Summer in the Hamptons, Warren Leight's The Night We Never Met, Anthony Minghella's Mr. Wonderful, Alan Rudolph's The Moderns and Sydney Pollack's Random Hearts.

A 1996 Sundance Filmmakers Lab participant, Smith wrote, produced and directed the award-winning short film Sheeps Meadow, which has aired on the Sundance Channel. She recently produced, directed and shot Honky: Portrait of a Bluesman, a documentary about Chicago bluesman Jake La Botz, and is currently finishing a documentary on Zimbabwe's Painted Hunting Dogs.

For television, she has appeared on such series as Law and Order: Criminal Intent, Sidney Lumet's 100 Centre Street, Big Apple, Homicide: Life on the Street, The Larry Sanders Show, Law and Order, Showtime's The Hunger and TNT's A Century of Women. Her stage work includes Stop Kiss at The Public Theater and Andre Gregory's production of Uncle Vanya at the Victory Theater the basis for Louis Malle's subsequent screen adaptation.

Her TV appearances most famously include her portrayal of Dr. Erica Hahn in five episodes of Grey's Anatomy, her portrayal of Dr. Kate Switzer on Crossing Jordan (She appeared in thirteen of the episodes of the sixth season, credited as a guest star), her appearance on Six Feet Under as one of Claire Fisher's art teachers, and most recently her appearance on Weeds (TV series) as the ex-wife of Peter Scottson (late husband of main character Nancy Botwin).

Smith returned to her role as Dr. Erica Hahn in Season 4 of Grey's Anatomy, in episode 5 "Haunt You Every Day", in which it was announced that Dr. Hahn would become the hospital's head of cardiothoracics, sealing Brooke Smith as the series newest season regular. At the same time, Brooke originated the role of Andrea in pilot of the new Abcdrama Dirty Sexy Money, but would be replaced by Sheryl Lee after her promotion at Grey's Anatomy.