He began his top-tier racing career in the IndyCar Series, making his driving debut during the 2000 season for PDM Racing. Hornish began driving for Panther Racing the following season, winning eleven races and the 2001 and 2002 series championships over the next three seasons. During the 2004 season Hornish began driving for Team Penske, winning eight more races (including the 2006 Indianapolis 500) and the 2006 series championship during his time with the team. When he left the series after the 2007 season, he held the record for most career wins in the series (19, broken by Scott Dixon in 2009).