His musical education started with recorder classes as a schoolboy, then violin lessons, eventually choosing trumpet as his instrument. When he was 14, Harding decided he wanted to be a conductor, conducting Schoenberg's Pierrot Lunaire with his school orchestra the next year. Harding wrote to Simon Rattle about this performance. Rattle, who himself had great success at an early age, says that when he saw the letter he thought Harding was "crazy." Nevertheless, when he came to see for himself, Rattle was impressed. At the age of 17, Harding became Rattle's assistant. This resulted in his professional conducting debut in 1994 with the City of Birmingham Symphony Orchestra.
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.
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.