The key issues clinicians are facing regarding drotrecogin alfa (activated) include questions concerning the pathophysiology and appropriate patient selection for administration of this drug. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the efficacy of drotrecogin alfa (activated) was demonstrated in patients with severe sepsis. Because of this trial's strict inclusion and exclusion criteria, however, the applicability of the study criteria to different types of patients raises important issues. Coupling the data from the PROWESS trial with additional information being gained from expanding clinical experience, as well as additional studies, clinicians will be able to better understand and refine the use of activated protein C within their respective practices.