Sepsis is the leading cause of death in surgical intensive care units and is a major cause of morbidity and mortality in neonatal and medical intensive care units. The Centers for Disease Control and Prevention estimates that, in the United States alone, ∼500,000 people develop sepsis and 175,000 people die each year. Sepsis is a growing problem; its incidence has tripled from 1972 to 1992. Recently, apoptosis has been identified as an important mechanism of cell death in animal models of sepsis and endotoxemia. During sepsis, there is extensive apoptotic death of lymphocytes and gastrointestinal epithelial cells. The extensive apoptotic death of lymphocytes is likely an important cause of the profound immunosuppression that is a hallmark of patients with sepsis. The apoptosis of gastrointestinal epithelial cells may compromise the integrity of the bowel wall, resulting in translocation of bacteria or endotoxins into the systemic circulation. The potential importance of apoptosis in the pathophysiology of sepsis is illustrated by results from animal models that demonstrate that blocking lymphocyte apoptosis improves survival in sepsis. A variety of strategies to inhibit apoptosis may ultimately provide an effective therapy for this highly lethal disorder.