Academic health centers (AHCs) have opportunities to advance the agenda of U.S. health care reform by tying the needs of populations to the AHCs' missions and areas of expertise. Serving as accountable care organizations and advancing the agenda of the patient-centered medical home are two important potential actions AHCs can take. By fostering discovery, learning, and care through rational organizational structures that meet the needs of populations and bend the curve of growing health care expenditures, AHCs can lead health care reform in the 21st century.