With growing constraints on government spending, policy makers are investing in comparative effectiveness research (CER) to attempt to bring the power of science to bear on the problems of suboptimal outcomes and high cost in the U.S. health care system. This commitment of resources to CER reflects confidence that better evidence can help clinicians and patients make better decisions, consistent with the long tradition of medical schools' and teaching hospitals' use of science to inform medical care. Thus, CER offers a great opportunity, albeit with some considerable challenges, for academic medicine to play a central role in comprehensive health care reform. Certainly, many scientists conducting CER will learn their methodological rigor in the training programs of academic health centers. Numerous new CER research teams will be needed, establishing effective partnerships far outside the walls of the traditional academic setting. And the clinicians interpreting the medical literature and applying the insights from CER to the unique problems of individual patients will need to learn this evidence-based, patient-centered care from the educators, mentors, and role models at U.S. medical and other health science schools and teaching hospitals. Achieving this will require investment in research infrastructure, adaptations of institutional culture, development of new disciplines and research methods, establishment of new collaborations, training of new faculty, and the expansion and refocusing of educational capacity. By successfully responding to this challenge, academic medicine can further strengthen its long-standing commitment to the scientific practice of medicine and the use of evidence in patient-centered, personalized care.