Containing growth in health care expenditures is considered to be essential to improving both the long-term fiscal outlook of the federal government and the future affordability of health care in the US. As health care expenditures have increased, so too have concerns about the quality of health care. Better information on the clinical effectiveness of alternative treatments and other interventions is needed to improve the quality of care and restrain growth in expenditures. This article explains the key role played by the federal government in defining the context and process of comparative effectiveness research as well as its funding. Subsequently, the article explores the mission, priorities, and research agenda of the Patient-Centered Outcomes Research Institute, which is an independent, nonprofit corporation established in 2010 by the Patient Protection and Affordable Care Act.