Smith started her career in 1970 as a model, working for such brands as Chanel, Versace, Geoffrey Beene, Issey Miyake, Norma Kamali, Thierry Mugler, and Patrick Kelly. She also modeled for her brother's line.
She also had a successful print career, including a photo campaign for Yves St. Laurent as well as appearances in Vogue, ELLE, Ebony, Cosmopolitan, Redbook, and Seventeen magazines. In 1978, Smith was named Bloomingdale's Model of the Year and became the first African–American model to have a mannequin designed in her likeness.
From 1988–1996, Smith's long–term partner was actor Robert De Niro, with whom she had twin sons (Aaron Kendrick De Niro and Julian Henry De Niro; born 1995) conceived by in vitro fertilization and delivered by a surrogate mother.
Besides 227, Her other credits include Talkin' Dirty After Dark (1991), Joe's Apartment (1994), and The Preacher's Wife (1996).