Identification of good surrogate end-points can greatly facilitate the design of clinical trials. Using data from PROWESS and ENHANCE, Shorr and colleagues explore the potential value of several plasma biomarkers for treatment trials of activated protein C for severe sepsis. Based on the framework proposed by Vasan, they tested the utility of several factors (protein C, interleukin-6, antithrombin III, prothrombin time, protein S, and d-dimers) as type 0, 1 and 2 biomarkers. Only protein C had acceptable performance characteristics as a type 2 biomarker, or surrogate end-point. The utility of protein C as a surrogate end-point for studies of severe sepsis must be validated in future prospective studies.