In the United States, more than $16 billion annually is spent managing patients with severe sepsis and its sequelae. Insight into the inflammatory response, endothelial tissue, and the coagulation cascade suggest promising new treatment regimens that limit morbidity and mortality due to sepsis and multisystem organ failure. This article will discuss new information regarding the pathophysiology of the inflammatory response and sepsis. Current thoughts on clinical management and a promising new agent, Activated Protein C, will be presented.