The environment for clinical trials in sepsis has long been identified as challenging and full of road blocks and land mines. Unlike many other diagnoses (ie, cancer, acute myocardial infarction) relevance of animal studies and predictive capability of phase II trials for dose generation is less clear. The members of the investigative team must realize the essentials for success in a multicenter clinical trial. It is also useful and important to understand the big picture of clinical trial development as well as properly functioning interfaces among sponsor, contract research organizations, and investigative sites. Because early enrollment into sepsis clinical trials is usually required, collaboration between emergency medicine and critical care is needed.