Nelson began as an actress performing with the acclaimed experimental theater group Mabou Mines. She went on to work with Raul Julia in the New York Shakespeare Festival production of "The Tempest" in Central Park as well as appearing in various NY productions before moving to L.A. Eventually growing frustrated with the paucity of worthwhile female roles, Nelson turned to screenwriting with her partner Stephen Tolkin. Finding that her control over her work was still limited, she decided to become a director.
Nelson helmed a nonfiction film, "My First Time", which brought her to the attention of Chanticleer Films' Discovery Program, a non-profit organization which helped industry professionals direct short fiction films. She wrote and directed "To the Moon Alice" (1990), a fantasy-tinged drama about a homeless family that takes nightly refuge on the empty set of a TV sitcom. Broadcast on cable as a "Showtime 30-Minute Movie", this paved the way to "Corrina, Corrina".
After working on the screenplays to "Stepmom" (1998) and "The Story of Us" (1999), Nelson wrote, produced and directed "I Am Sam" (2001), a slightly treacly tale of a mentally-challenged man seeking custody of his young daughter. The film was most notable for bringing star Sean Penn his third Best Actor Oscar nomination.