Despite spectacular advances in life-support technology, the management of patients with severe sepsis continues to be a significant health care challenge because of the associated major morbidity, high mortality, and health economic implications. Severe sepsis with associated multisystem organ dysfunction (MOD) is the leading cause of death in the intensive care unit. Recent understanding of the pathophysiology now demonstrates that the syndrome of severe sepsis after a major physiologic insult is characterized by the activation of multiple overlapping and interacting cascades leading to systemic inflammation, a procoagulant state, and decreased fibrinolysis, which if unchecked leads to the progressive functional deterioration of multiple interdependent organs. This review will highlight the epidemiology, current understanding of the pathophysiology, management, and prevention of the syndrome of severe sepsis with MOD.