In 1998, the Institute of Medicine (IOM) issued a report on medical errors, which estimated that up to 98,000 people die in U.S. hospitals each year from errors. This report raised concerns that medical errors have become a national public health problem that should be addressed in the same manner as other epidemics such as heart disease, diabetes, and obesity. In 2001, the IOM released a follow-up report encompassing a broader range of quality issues. They concluded that the U.S. healthcare system is outmoded and incapable of providing consistent, high-quality care. They outlined a strategy for redesigning U.S. healthcare delivery to achieve safe, dependable, high-quality care, which emphasizes information technology as an integral part of the solution. AHRQ’s fiscal year 2001 appropriation included $50 million dollars for initiatives to reduce medical errors and improve patient safety. AHRQ responded to this mandate by developing a series of research solicitations that form an integrated set of activities to design and test best practices for reducing errors in multiple health care settings. This paper discusses the components of this program and the central role of medical informatics research in the Agency’s efforts to improve the safety of medical care in America.