The mortality from septic shock continues to range between 40% to 60% despite advances in cardiovascular support and antibiotic therapy. Impairment of host defenses predisposes to the development of both severe infection and septic shock. The activation of a myriad of cellular and plasma mediators by microbial toxins produces the systemic and metabolic manifestations of sepsis. The clinical presentation includes characteristic clinical, hemodynamic, and laboratory abnormalities. Multiple organ systems are involved during septic shock, with outcome dependent on the circulatory response and the development of sequential organ failures. Initial resuscitation is directed at restoring tissue perfusion with fluids and vasoactive drugs, guided by assessment of the patient's hemodynamic status. Identification of the site of infection and choice of appropriate antibiotics are critical to the success of therapy. Newer therapeutic modalities include immunologic interventions that attenuate mediator activity and modulate the immune response. Pharmacologic therapies are also being developed that are aimed at blocking the actions of specific mediators.