PURPOSE: Comparative effectiveness research (CER) is designed to support informed decision making at both the individual, population, and policy levels. The American College of Sports Medicine and partners convened a conference with the focus of building an agenda for CER within the context of physical activity and nonpharmacological lifestyle approaches in the prevention and treatment of chronic disease. This report summarizes the conference content and consensus recommendations that culminated in a CER roadmap for physical activity and lifestyle approaches to reducing the risk of chronic disease. METHODS: This conference focused on presentations and discussion around the following topic areas: 1) defining CER, 2) identifying the current funding climate to support CER, 3) summarizing methods for conducting CER, and 4) identifying CER opportunities for physical activity. RESULTS: This conference resulted in consensus recommendations to adopt a CER roadmap for physical activity and lifestyle approaches to reducing the risk of chronic disease. In general, this roadmap provides a systematic framework by which CER for physical activity can move from a planning phase to a phase of engagement in CER related to lifestyle factors with particular emphasis on physical activity to a societal change phase that results in changes in policy, practice, and health. CONCLUSIONS: It is recommended that physical activity researchers and health care providers use the roadmap developed from this conference as a method to systematically engage in and apply CER to the promotion of physical activity as a key lifestyle behavior that can be effective at making an impact on a variety of health-related outcomes.