She wrote novels and stories in the science fiction, mystery, and suspense genres, including the Hugo Award–winning Where Late the Sweet Birds Sang.

Wilhelm established the Clarion Workshop along with her husband Damon Knight and writer Robin Scott Wilson.

[3] Her first published short fiction was "The Pint-Size Genie" in the October 1956 issue of Fantastic, edited by Paul W. Fairman (assisted by Cele Goldsmith, who was responsible for looking at unsolicited submissions to the magazine).

The Science Fiction and Fantasy Hall of Fame inducted Wilhelm in 2003, its eighth class of two deceased and two living writers.

She and her semi-retired lawyer father, Frank Holloway, solve mysteries that combine detective fiction with courtroom drama.