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Danielle Harris auditioned for the part of Jamie Lloyd (Michael Myers's niece) in the 1988 movie Halloween 4: The Return of Michael Myers (which she won). The next year, she reprised the role in Halloween 5: The Revenge of Michael Myers.

The character of Jamie returned in 1995 for Halloween: The Curse of Michael Myers, but Danielle did not participate due to disagreements on her fate in the script. Also, Harris reportedly requested $5000 to appear in the film (far less than she was paid for Halloween 4), but no agreement could be reached. J.C. Brandy ended up playing the roll of Jamie in the film, a decision in which some fans of the Halloween series were said to be dissatisfied, since Danielle had become very popular with many fans.

Harris would later return to the franchise in a new role, playing Annie Brackett, in Rob Zombie's Halloween, a 2007 re-imagining of John Carpenter's 1978 original horror masterpiece. In the 2007 remake she posed nude for a sex scene which caused some controversy. She stated "I want people to see me in this movie as Annie Brackett, not Jamie. I'm not little Jamie anymore and people need to realize that." She reprised her role in Rob Zombie's Halloween II, released in 2009.

Harris's other film credits include Marked for Death (1990) alongside Steven Seagal, Don't Tell Mom the Babysitter's Dead (1991) alongside Christina Applegate, City Slickers (1991), The Last Boy Scout (1991) alongside Bruce Willis and Damon Wayans, Free Willy (1993), Daylight (1997) alongside Sylvester Stallone, Wish Upon a Star (1996) alongside Katherine Heigl, and Urban Legend (1998). She has also appeared frequently on television, with a recurring role on the sitcom Roseanne during the 1992-93 season (as Roseanne's neighbor Molly), and subsequent guest appearances on Boy Meets World, Diagnosis Murder, Charmed, ER and Cold Case.

Some of Harris's most recent projects include the films Debating Robert Lee, Race You to the Bottom (an Outfest Prize Winner), Blood Night: The Legend of Mary Hatchet and Left for Dead, as well as an appearance in the music video for the song "The Bleeding", by Five Finger Death Punch. She also stars alongside Lance Henriksen, Bill Moseley, AFI's Davey Havok, and Battlestar Galactica's Nicki Clyne in the "illustrated film" series Godkiller.

Harris is a guest star of the 2010 Creation Entertainment Weekend of Horrors in the Marriott Los Angeles Airport on 21 May 2010.