The Institute for Healthcare Improvement's (IHI’s) 5 Million Lives Campaign targets a reduction of five million instances of harm from December 2006 through December 2008. Together with complementary partner initiatives, the Campaign is intended to act as a major driver of national improvement. This article, the first in a series, gives an overview of the predecessor 100,000 Lives Campaign, and describes the 5 Million Lives Campaign and its six new interventions.