After conducting a number of European youth orchestras, Welser-Möst gained favorable attention and worldwide notice as a conductor with the London Philharmonic (1986), which he led during a successful European tour. From that point, he found himself in constant demand as a guest conductor. Among the more notable of his engagements were his operatic debut (conducting Rossini's L'italiana in Algeri at the Vienna State Opera in 1987) and his American debut (conducting the St. Louis Symphony in 1989).

Welser-Möst's first important permanent position was as director of the London Philharmonic, a post he assumed in 1990; in 1995 he became music director of the Zürich Opera. In 1999, Welser-Möst received the most lucrative and prestigious appointment of his career: directorship of the Cleveland Orchestra (beginning in 2002), replacing the departing Christoph von Dohnányi. That contract continued through the 2010-2011 season and beyond. He was also appointed music director of the Vienna State Opera in 2008 and he conducted the Vienna New Year's Concert in 2010/2011.

Welser-Möst boasts an extensive discography, which is highlighted by notable recordings of Bruckner, Stravinsky, and Franz Schmidt; his recording of Schmidt's Symphony No. 4 and Variations on a Hussar's Song won the Gramophone Orchestral Award in 1996.