After playing a small part in Martin Scorsese's Alice Doesn't Live Here Anymore (1974), Dern landed her first major role in the teen movie Foxes (1980). In 1985, she showed her versatility in Mask and Smooth Talk, portraying two very disparate characters. Next came roles in the David Lynch films Blue Velvet and Wild at Heart. Dern received an Oscar nomination for her performance in Rambling Rose, as did Diane Ladd, who co-starred, making them the first mother-daughter duo to earn simultaneous nominations.
Other notable films include Afterburn (for which she received an Emmy nomination and a Golden Globe), I Am Sam, Citizen Ruth, We Don't Live Here Anymore and Inland Empire (another Lynch-directed film). Dern was also Emmy- and Golden Globe-nominated for her role in Recount (2008).