In 1985, when Heche was sixteen, an agent spotted her in a school play and secured her an audition for the daytime soap opera As the World Turns. Heche flew to New York City, auditioned, and was offered a job, but her mother insisted she finish high school first. Shortly before her high school graduation in 1987, Heche was offered a dual role on the daytime soap opera Another World.
For her work on Another World, Heche received a Daytime Emmy Award for Outstanding Younger Actress in a Drama Series in 1991. In November 1991, Heche made her primetime television debut in an episode of Murphy Brown. She made her TV-movie debut the following year with a brief appearance in the Hallmark Hall of Fame presentation of O Pioneers! (1992). In 1993, Heche made her feature film debut in Disney's The Adventures of Huck Finn with Elijah Wood. Over the next two years, she had small supporting roles in made-for-TV movies such as Girls in Prison and Kingfish: A Story of Huey P. Long.
In 1996, Heche landed her first substantial role as a college student contemplating an abortion in a segment of the made-for-HBO anthology film If These Walls Could Talk, co-starring Cher and Demi Moore. Also in the year, she appeared opposite Natalie Portman portraying childhood best friends in the independent film Walking and Talking. The limited released film garnered favorable reviews from critics and is #47 on Entertainment Weekly's "Top 50 Cult Films of All-Time" list.
In 2002, Heche made her Broadway debut in a production of the Pulitzer Prize-winning drama Proof, acting as a young woman who has inherited from her father mathematical genius and his madness. In 2004, Heche received a Primetime Emmy Award nomination for Best Supporting Actress for her performance in the Lifetime movie Gracie's Choice, as well as a Saturn Award nomination for Best Actress for her performance in the CBS television film The Dead Will Tell. In the same year, she acted opposite Alec Baldwin in Broadway's Twentieth Century, about a successful and egomaniacal Broadway director (Baldwin), who has transformed a chorus girl (Heche) into a leading lady. For her performance, she was nominated for the 2004 Tony Award for Best Actress in a Play.
USA Network's action adventure drama series, Dig, saw Heche portray the head of the FBI office in Jerusalem whose agents uncovers a 2,000-year-old conspiracy while investigating an archaeologist's murder. The six-episode series premiered late 2014. In 2015, Heche guest-starred in the ABC thriller series Quantico playing the role of criminal profiler, Dr. Susan Langdon. On September 27, 2016, the post-apocalyptic action drama Aftermath –starring Heche– debuted on Canada's Space Network and on United States' Syfy. Heche played Karen Copeland, a Air Force pilot from Washington State who must navigate Armageddon, along with her university-professor husband Josh (played by James Tupper, also a co-producer on the series) and their three nearly-adult children.
Heche will star in the upcoming NBC drama The Brave.
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