Sepsis, a life-threatening disorder that arises through the body's response to infection, is the leading cause of death and disability for patients in an intensive care unit. Advances in the understanding of the complex biological processes responsible for the clinical syndrome have led to the identification of many promising new therapeutic targets, including bacterial toxins, host-derived mediators, and downstream processes such as coagulation and the endocrine response. Diverse therapies directed against these targets have shown dramatic effects in animal models; however, in humans, their impact has been frustratingly modest, and only one agent — recombinant activated protein C — has achieved regulatory approval. This review summarizes the approaches that have been evaluated in clinical trials, explores the reasons for the discordance between biological promise and clinical reality, and points to approaches that may lead to greater success in the future.