Background: Healthcare expenditures in the United States exceed the healthcare expenditures of other countries, yet relatively unfavorable health outcomes persist. Despite the emergence of numerous evidence-based interventions, wide variations in clinical care have caused disparities in quality of care and cost. Comparative effectiveness and cost effectiveness research may better guide healthcare decisionmakers in determining which interventions work best, for which populations, under which conditions, and at what cost.; Methods: This article reviews national health policies that promote comparative effectiveness research (CER), healthcare decisionmaker roles in CER, methodological approaches to CER, and future implications of CER.; Results: This article provides a brief summary of CER health policy up to the Patient Protection and Affordable Care Act and its establishment of the Patient-Centered Outcomes Research Institute (PCORI). Through PCORI, participatory methods for engaging healthcare decisionmakers in the entire CER process have gained momentum as a strategy for improving the relevance of research and expediting the translation of research into practice. Well-designed, methodologically rigorous observational studies and randomized trials conducted in real-world settings have the potential to improve the quality, generalizability, and transferability of study findings.; Conclusion: Learning health systems and practice-based research networks provide the infrastructure for advancing CER methods, generating local solutions to high-quality cost-effective care, and transitioning research into implementation and dissemination science-all of which will ultimately guide health policy on clinical care, payment for care, and population health.