An estimated 750,000 cases of severe sepsis occur annually in the United States, and the mortality rate is about 30%. As a condition that disproportionately affects the elderly and is related to invasive and immunosuppressive healthcare, increases in the frequency of sepsis are anticipated. The complex pathophysiology of sepsis encompasses the interplay of pro- and anti-inflammatory mediators, activated circulating and resident inflammatory cells, disrupted coagulation, endothelial activation and injury, vasodilatation and vascular hyporesponsiveness to vasoactive mediators, cardiac dysfunction, and cellular dysoxia. Current management of severe sepsis includes eradication of infection through source control and antimicrobial therapy, aggressive and targeted shock resuscitation that includes fluid administration, correction of anemia, vasopressor support, modest inotropic therapy, infusion of human recombinant activated protein C to selected patients, and compulsive supportive care to manage organ dysfunction and to avoid complications.