The ability to manage risk depends critically on an understanding of the degree to which a known risk is balanced by the probability of a clinical benefit. Despite the massive emphasis on risk and risk management in the past few years and the long-term focus on defining benefit in the regulatory system, considerable uncertainty remains about the methods of defining benefit and how to operationalize this knowledge. In this 'think tank,' part of a larger series on risk management, issues were divided into those that can be identified before a study is initiated, those that commonly arise after a study is completed, biomarkers and surrogates, use of benefit findings in defining quality and performance indicators, implementation of findings into health systems and formularies, and methods of comparative trials. Key categories for the establishment of a research agenda to fill in gaps in our understanding of assessing benefit were developed by the group.