Harding was hired at the age of 18 by Hans Werner Henze to participate in the preparations for the Munich Biennial Festival, the same year Pierre Boulez accepted Harding into his master class. Claudio Abbado engaged Harding as assistant conductor of the Berlin Philharmonic for the 1995-1996 season.
During the September 1996 Berlin Festival, Harding received a quintessential lucky break when conductor Franz Welser-Möst fell ill. Without a rehearsal, he took over the podium in a program of Berlioz's Corsair Overture, Brahms' Double Concerto, and Dvorák's Symphony No. 8 in G major. The critic of the Berlin Zeitung said that after a momentary sense of nervousness at the start of the concert, Harding led the overture with verve and authority. She praised his alert and sympathetic accompanying of the two soloists in the concerto, and his grasp and elucidation of an over-all line in the symphony while still attentive to the work's details.
In 1996 Harding also became the youngest conductor ever to give a concert in the BBC Proms. In 1997 he became principal conductor of the Trondheim (Norway) Symphony Orchestra. He also was guest conductor of the Norrkoping Symphony Orchestra in Sweden, and with the Mahler Chamber Orchestra, where he became principal conductor (2003-2011). In autumn 1997, he took up the position of music director of the Deutsche Kammerphilharmonie, leaving there in 2003.
He has guest conducted widely and also conducted opera, leading Janácek's Jenufa (Welsh National Opera) and Mozart's Don Giovanni (with a touring company featuring the Mahler Chamber Orchestra). His Royal Opera House debut was in Britten's Turn of the Screw, and he has been at La Scala a number of times since 2005.
He had something of a dream come true when, in 1998, he returned to the BBC Proms to conduct the Scharoun Ensemble (whose members are drawn from the Berlin Philharmonic) in Pierrot Lunaire.
His first release with Virgin Records was music of Schoenberg and Britten, and with the Kammerphilharmonie has recorded Beethoven overtures. Since then, he has recorded with the London Symphony Orchestra on EMI, and the Swedish Radio Symphony Orchestra, which he has led since 2007, on Sony.