Fleming's first major break came in 1988 when she sang the Countess in The Marriage of Figaro at the Houston Grand Opera. In 1989, she made debuts with the New York City Opera and the Royal Opera House, Covent Garden. In 1991, she made her Metropolitan Opera debut. In 1997, Fleming sang her first Manon at the Opéra Bastille to glowing reviews.
As a youngster, Fleming enjoyed popular music and admired the talent of Joni Mitchell and others. In addition to the standard operatic repertoire, she performs new music, Broadway show tunes, and other popular genres.
Fleming sang in the world première of John Corigliano's The Ghosts of Versailles with the Metropolitan Opera, in the Lyric Opera of Chicago's first performances of Floyd's Susannah, and as Blanche in the world première of André Previn's A Streetcar Named Desire, with the San Francisco Opera.