The daughter of detective novelist, C. W. Grafton, she said the strongest influence on her crime novels was author Ross Macdonald.

[2] Her father was a municipal bond lawyer who also wrote mystery novels, and her mother was a former high school chemistry teacher.

[3] Her father enlisted in the Army during World War II when she was three and returned when she was five, after which her home life started falling apart.

[8] Grafton's mother killed herself in 1960 after returning home from an operation to remove esophageal cancer brought on by years of drinking and smoking.

[12] Grafton worked for the next 15 years writing screenplays for television movies, including Sex and the Single Parent; Mark, I Love You; and Nurse.

In collaboration with her husband, Steven Humphrey, she also adapted the Agatha Christie novels, A Caribbean Mystery and Sparkling Cyanide, for television and co-wrote A Killer in the Family and Love on the Run.

[14][15] Her experience as a screenwriter taught her the basics of structuring a story, writing dialogue, and creating action sequences.

[13] While going through a "bitter divorce and custody battle that lasted six long years", Grafton imagined ways to kill or maim her ex-husband.

[19] Grafton described Kinsey Millhone as her alter ego, "the person I might have been had I not married young and had children.

[23] She refused to sell the film and television rights, because writing screenplays "cured" her of the desire to work with Hollywood.

[10] They divided their time between Santa Barbara, California, and Louisville, Kentucky;[5] Humphrey taught at universities in both cities.

[16] In 2000, the couple bought and later restored Lincliff, a 28-acre (11 ha) Louisville estate once owned by hardware baron William Richardson Belknap.

[5][33] Grafton died at Cottage Hospital in Santa Barbara on December 28, 2017, after a two-year battle with cancer of the appendix.

[35] Grafton's introduction of a young, no-nonsense female private detective in the Alphabet Mystery series was ground-breaking at the time when A is for Alibi was first released in 1982.