Metcalf began her professional career in the late 80s as a cast member at Chicago's famed Steppenwolf Theatre alongside famous performers like John Malcovich, Gary Sinese and Glenne Headly. Soon she was brought on as a performer on Saturday Night Live for their 1981 cast.
She performed as a character actress in several movies in the 80s including Desperately Seeking Susan, Making Mr. Right and the Martha Plimpton vehicle Star and Bars. It wasn't long before television producers took notice and she was cast as Jackie, sister to the title character in the hit series Roseanne.
Roseanne ran from 1988 to 1997 and Metcalf was a consistent castmember, receiving critical praise for her portrayal of the kooky sister. She won three Emmy awards for the role. During the show's run she continued appearing in movies, generally as the goofy or nutty best-friend. She appeared in Uncle Buck, JFK, A Dangerous Woman, Blink, The Secret Life of Houses, Toy Story and Leaving Las Vegas throughout her run on Roseanne.
Although Metcalf has continued to appear in supporting film roles since the end of her run on Roseanne she is probably best remembered as the murderous mother of Billy Loomis in her appearance in the horror film Scream 2. Metcalf is currently featured in the Nathan Lane series "Charlie Lawrence", which is receiving negative critical review. She is the mother of two.