A publicist for Lange confirmed the split Monday. People magazine first reported the separation, saying the actors concluded their relationship almost two years ago.
The 62-year-old Lange and the 68-year-old Shepard had been together since 1982. They have two grown children together.
Lange won Oscars for her roles in "Tootsie" and "Blue Sky." She's starring in the FX series "American Horror Story." She was nominated for a Golden Globe last week.
Shepard recently starred as Butch Cassidy in the film "Blackthorn." He also is a playwright and author whose play "Buried Child" won a Pulitzer Prize.
Lange previously was married to ballet dancer Mikhail Baryshnikov. Shepard previously was married to actress O-Lan Jones.