Metcalf began her career with the Steppenwolf Theater Company and frequently works in Chicago theater, including the 1983 revival of Balm in Gilead. From 1988 to 1997 and in 2018, Metcalf played the role of Jackie Harris on the ABC sitcom Roseanne, for which she won three Primetime Emmy Awards for Outstanding Supporting Actress in a Comedy Series (1992–1994). She also was nominated for two Golden Globe Awards. A ten-time Emmy Award nominee, Metcalf's television credits include 3rd Rock from the Sun, The Norm Show, Frasier, Desperate Housewives, and The Big Bang Theory. From 2013 to 2015, she played a leading role of Dr. Jenna James in the HBO comedy series Getting On, for which she received critical acclaim and a nomination for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series.