In recent years, the focus on comparative effectiveness research (CER), the funding available to support it, and the range of possible effects of CER policy on academic health centers (AHCs) have increased substantially. CER has implications for the research, education, and clinical care components of AHCs' missions. The current funding and policy environment have created specific opportunities for AHCs to shape and respond to CER policies across the four dimensions of the CER enterprise: research, human and scientific capital, data infrastructure, and translation and dissemination. Characteristics such as the degree of physician-hospital integration, the status of a health information technology infrastructure, and the presence of a well-developed cross-functional health services research capacity linked to the care delivery enterprise could help AHCs respond to these opportunities and influence future policies. AHCs are also essential to the development of methodologies and the training of the next cadre of researchers. Further, a focus on understanding what works in health care and increasing adoption of evidence-based practice must become embedded in the fabric of AHCs. Those AHCs most successful in responding to the CER challenge may leverage it as a point of differentiation in the marketplace for health care and lead transformational improvements in health.