It took Lange several years after her debut to find another screen role. Her then boyfriend Bob Fosse cast her as the Angel of Death in "All That Jazz" (1979) and she co-starred with TV refugees Susan Saint James and Jane Curtin in the comedy "How to Beat the High Cost of Living" (1980). But it was her turn in the Lana Turner role of a sultry femme fatale opposite Jack Nicholson in Bob Rafelson's remake of "The Postman Always Rings Twice" (1981) that made critics and audiences realize her abilities, despite its less than stellar box office.

Lange finally proved her versatility and attained star status with two 1982 roles, as 1930s actress Frances Farmer in the biopic "Frances" and as Dustin Hoffman's love interest in "Tootsie"; the first won her a Best Actress Oscar nomination and the second, the award for Best Supporting Actress. She racked up three more nominations by the end of the decade: as a stalwart farm wife opposite her real life companion Sam Shepard in "Country" (1984), which she also co-produced; as country music legend Patsy Cline in the biopic "Sweet Dreams" (1985); and for her searching, intelligent performance as the unsuspecting daughter of an alleged war criminal in Costa-Gavras' "Music Box" (1989).

In 1992, Lange made her Broadway debut in the celebrated role of Blanche DuBois opposite Alec Baldwin's Stanley Kowalski in Tennessee Williams' "A Streetcar Named Desire". Both she and Baldwin reprised their roles on a 1995 CBS movie. Lange's earlier TV work included another Williams heroine, Maggie, in "Cat on a Hot Tin Roof" (Showtime, 1984) and as a Minnesota farmer in the "Hallmark Hall of Fame" adaptation of Willa Cather's "O Pioneers!" (CBS, 1992).

Devoting more time to child-rearing, Lange worked less frequently in the late 1980s and early 90s. She worked with Robert De Niro in two high profile noir remakes, Martin Scorsese's "Cape Fear" (1991) and Irwin Winkler's "Night and the City" (1992). Lange was widely acclaimed and received a second Oscar, as Best Actress, for her performance in Tony Richardson's "Blue Sky" (completed in 1990; released 1994). She was Carly, the sensuous "woman-child" wife of a military nuclear engineer, whose tendency to act out her frustrations lead to domestic and professional complications for her family. Lange had two more successes with "Losing Isaiah" (1995), as a social worker who adopts a crack baby, and "Rob Roy" (also 1995), as the great love of the 18th-century Scottish freedom fighter (Liam Neeson). Lange frequently appeared opposite female co-stars that would push and challenge, such her roles in "A Thousand Acres" (1997) playing sister to Michelle Pfieffer and Jennifer Jason Leigh in a modern King Lear allegory; bedeviling unwanted daughter-in-law Gwyneth Paltrow in the thriller "Hush" (1998); and as the lonely spinster seamstress to courtesan Elizabeth Shue who slowly destroys the lives of those who've scorned her in the film adaptation of novelist Honoré de Balzac's "Cousin Bette" (1998).

Returning to Shakespeare, Lange made for a truly ferocious Tamora in "Titus" (1999), Julie Taymor's mind-bending, ultra-violent adaptation of Titus Andronicus, but was miscast in the long-delayed "Prozac Nation" (2001) as Elizabeth Wurtzell's (Christina Ricci) neurotic Jewish mother. The actress was far more effective in the HBO telepic "Normal" (2003) as a wife whose husband of 25 years (Tom Wilkinson) suddenly reveals that he wants a sex change operation; Lange was rewarded with Emmy, Golden Globe and Golden Satellite nominations for her performance. Next she essayed the role of the older Sandra Bloom, who husband was given to fanciful self-mythologizing, in director Tim Burton's "Big Fish" (2003). She next appeared in Jim Jarmush’s “Broken Flowers” (2005), playing one of four ex-girlfriends of a man (Bill Murray) who tracks down his former lovers after receiving an anonymous letter from the mother of his heretofore unknown son.

From 1970 to 1982, Lange was married to photographer Paco Grande. She was romantically involved with dancer-actor Mikhail Baryshnikov from 1976 to 1982. Since 1982, Lange has lived with playwright-actor Sam Shepard with whom she acted with in "Frances" (1982), "Country" (1984) and "Crimes of the Heart" (1986) and who directed her in "Far North" (1988).