Pfeiffer was cast against type, as a murdered gangster's widowed moll on the run, in Jonathan Demme's mafia comedy Married to the Mob (1988), opposite Matthew Modine, Dean Stockwell and Mercedes Ruehl. For the role of Angela de Marco, she donned a curly brunette wig and a Brooklyn accent, and received her first of six consecutive Golden Globe Best Actress Award nominations. Pfeiffer then appeared as chic restauranteuse Jo Ann Vallenari in Tequila Sunrise (1988) opposite Mel Gibson and Kurt Russell, but experienced creative and personal differences with director Robert Towne, who later described her as the "most difficult" actress he's ever worked with.

At Demme's personal recommendation, Pfeiffer joined the cast of Stephen Frears's Dangerous Liaisons (1988) alongside Glenn Close and John Malkovich, playing the virtuous victim of seduction, Madame Marie de Tourvel. Her performance won her widespread acclaim; Hal Hinson of the Washington Post saw Pfeiffer's role as "the least obvious and the most difficult. Nothing is harder to play than virtue, and Pfeiffer is smart enough not to try. Instead, she embodies it. Her porcelain-skinned beauty, in this regard, is a great asset, and the way it's used makes it seem an aspect of her spirituality." She won the BAFTA Award for Best Actress in a Supporting Role and received a nomination for the Academy Award for Best Supporting Actress.

Pfeiffer then accepted the role of Susie Diamond, a hard-edged former call girl turned lounge singer, in The Fabulous Baker Boys (1989), which co-starred Jeff Bridges and Beau Bridges as the eponymous Baker Boys. She underwent intensive voice training for the role, and performed all of her character's vocals. The film was a modest success, but Pfeiffer's portrayal of Susie drew unanimous raves from critics. Pauline Kael wrote of the performance as possessing "the grinning infectiousness of Carole Lombard, [and] the radiance of the very young Lauren Bacall," while Roger Ebert compared her to Rita Hayworth in Gilda and Marilyn Monroe in Some Like It Hot, and described the film as "one of the movies they will use as a document, years from now, when they begin to trace the steps by which Pfeiffer became a great star." Variety singled out her memorable performance of 'Makin' Whoopee', writing that Pfeiffer "hits the spot in the film's certain-to-be-remembered highlight... crawling all over a piano in a blazing red dress. She's dynamite." During the 1989-1990 awards season, Pfeiffer dominated the Best Actress category at every major awards ceremony, winning awards at the Golden Globes, the National Board of Review, the National Society of Film Critics, the New York Film Critics Circle, the Los Angeles Film Critics Association and the Chicago Film Critics Association. At the Academy Awards, she was the clear favourite to win the Best Actress Oscar, but the award went to Jessica Tandy for Driving Miss Daisy in what was considered a surprise upset. The only other major acting award she did not take home for The Fabulous Baker Boys was the BAFTA Award for Best Actress in a Leading Role, which also went to Tandy.

• Personal Effects (2009) .... Linda
• Chéri (2009) .... Lea de Lonval
• Stardust (2007) .... Lamia
• Hairspray (2007) .... Velma Von Tussle
• I Could Never Be Your Woman (2007) .... Rosie
• Sinbad: Legend of the Seven Seas (2003) (voice) .... Eris
• White Oleander (2002) .... Ingrid Magnussen
  ... aka Weißer Oleander (Germany)
• I Am Sam (2001) .... Rita Harrison Williams
• What Lies Beneath (2000) .... Claire Spencer
  
• The Story of Us (1999) .... Katie Jordan
• A Midsummer Night's Dream (1999) .... Titania
  ... aka Sogno di una notte di mezza estate (Italy)
  ... aka William Shakespeare's A Midsummer Night's Dream (USA: complete title)
• The Deep End of the Ocean (1999) .... Beth Cappadora
• The Prince of Egypt (1998) (voice) .... Tzipporah
• A Thousand Acres (1997) .... Rose Cook Lewis
• One Fine Day (1996) .... Melanie Parker
• To Gillian on Her 37th Birthday (1996) .... Gillian Lewis
• Up Close & Personal (1996) .... Sally 'Tally' Atwater
• Dangerous Minds (1995) .... Louanne Johnson
• "Picket Fences" .... Client (1 episode, 1995)
       - Freezer Burn (1995) TV episode (uncredited) .... Client
• Wolf (1994) .... Laura Alden