Medicine's current evidence base is insufficient for many of the decisions made daily by clinicians, patients, purchasers, and policy makers. The Patient-Centered Outcomes Research Institute represents an effort by the US government to address this shortcoming by funding comparative effectiveness research. Prioritizing that research will be a critical first step. To better understand components of an optimal process, we reviewed the literature and conducted interviews regarding the prioritization efforts of leading public and private health organizations in the United States and abroad. From this review, we propose a framework for prioritization, pose and answer key questions, and make recommendations regarding application of that framework. We also recommend that during the priority-setting process, there should be transparent conversations among those who make decisions about the priorities and the public.