ISSUE: The newly published report of the Second Panel on Cost-Effectiveness in Health and Medicine updates recommendations for the field in order to provide guidance for the next generation of practitioners and decision makers. In this issue panel, panelists, including members of the Second Panel, will highlight and debate key topics that arose during the panel’s deliberations and for which the panel believes that future research and policy would be particularly fruitful. Panelists will consider opportunities and challenges in: measuring costs (Basu); the use of cost-effectiveness thresholds (Basu & Sculpher); the role of cost-effectiveness analysis (CEA) in decision making (Sculpher & Neumann); improving the comparability, durability, and reliability of CEAs (Kim); and incorporating uncertainty and value of information analysis in decision making (Kim). Panelists will present each topic, review controversies that arose during the Second Panel’s deliberations, and discuss future research opportunities to advance the field. OVERVIEW: In the 20 years since publication of the report of the US panel on Cost Effectiveness in Health and Medicine, researchers have advanced methods of cost-effectiveness analysis (CEA) and policy makers have experimented with its application. Updating the original panel’s work provided the Second Panel on Cost-Effectiveness in Health and Medicine an opportunity to reflect on the evolution of CEA and to provide guidance for the next generation of practitioners and consumers. It also raised key areas for future research and policy development.