Dern's starring role in Blue Velvet was a breakthrough though her next notable film, Wild at Heart, took almost four years to be released.

Dern's affiliation with David Lynch has continued with her role in Inland Empire.

In 1992, Dern and her mother became the first mother and daughter to be nominated for an Academy Award for acting in the same film in Rambling Rose although, unlike in Wild at Heart, they did not play mother and daughter in the film. Ellie Sattler in Steven Spielberg's 1993 film Jurassic Park.

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She also made a brief appearance in Alice Doesn't Live Here Anymore (1974), one of Ladd's signature roles.

Her mother objected to her 13-year-old daughter's presence on the set of Ladies and Gentlemen, The Fabulous Stains, but Dern sued for and received emancipation.

Dern plays Amy Jellicoe, "a health and beauty executive who returns from a post-meltdown retreat to pick up the pieces of her broken life" with, among others, her mother, played by her real-life mother Ladd.

Dern brought screenwriter Mike White back into television work after he had had an on-the-job meltdown of his own.

In 1997, Dern was featured in Widespread Panic's music video for their song, "Aunt Avis", which was directed by Dern's then boyfriend and future fiancé, Billy Bob Thornton.

In 1998, Dern co-starred in Jodie Foster's film The Baby Dance.On the April 24, 2007 airing of De Generes's talk show, Dern revealed she did not work for more than a year following her appearance in that episode because of resulting backlash, but nevertheless called it an "extraordinary experience and opportunity." Dern has been acknowledged with several awards from the independent film industry including the Sundance Institute and was the subject of an aggressive media campaign by David Lynch to win her an Academy Award nomination for her work in Inland Empire.On November 1, 2010, she received the 2,420th star on the Hollywood Walk of Fame.Her parents, Diane Ladd and Bruce Dern, were also presented with stars.In October 2011, Dern starred in a new HBO television series called Enlightened.The poet, writer, and Librarian of Congress Archibald Mac Leish was her great-great-uncle.