Most health care recommendations in the United States have come from trials designed to measure efficacy of medical interventions, with randomized controlled trials considered the gold standard for evidence-based medicine. Comparative effectiveness research has become an essential component of research to help define the benefits, risks, and effectiveness of different interventions for a particular illness. Comparative effectiveness research is informally defined as an assessment of all available options for a specific medical condition, with intent to estimate effectiveness in specific subpopulations. In this article, we contrast efficacy-based healthcare research and recommendations in the United States, under the model of evidencebased medicine, to the contemporary paradigm of comparative effectiveness research. We review the recent emphasis by the federal government on comparative effectiveness research. Finally, we review the limitations of effectiveness and efficiency.