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Linney made her Broadway debut in 1990 before going on to receive Tony Award nominations for the 2002 revival of The Crucible, the original Broadway productions of Sight Unseen (2004), Time Stands Still (2010), My Name Is Lucy Barton (2020), and the 2017 revival of The Little Foxes. On television, she won her first Emmy Award for the television film Wild Iris (2001), and had subsequent wins for the sitcom Frasier (2003–04) and the miniseries John Adams (2008). From 2010 to 2013, she starred in the Showtime series The Big C, which won her a fourth Emmy in 2013, and from 2017 to 2022 she starred in the Netflix crime series Ozark.

Linney is also an established film actress. She made her film debut with a minor role in Lorenzo's Oil (1992) and went on to receive Academy Award nominations for the dramas You Can Count on Me (2000), Kinsey (2004), and The Savages (2007). She's also known for her performances in Primal Fear (1996), The Truman Show (1998), Mystic River and Love Actually (both 2003), The Squid and the Whale (2005), The Nanny Diaries (2007), Hyde Park on Hudson (2012), Mr. Holmes (2015), Sully and Nocturnal Animals (both 2016).