The incidence of the sepsis syndrome has increased dramatically in the last few decades. During this time, we have gained new insights into the pathophysiologic mechanisms leading to organ dysfunction in this syndrome. Yet, despite this increased knowledge and the use of novel therapeutic approaches, the mortality associated with the sepsis syndrome has remained between 30% and 40%. Appropriate antibiotic selection and hemodynamic support remain the cornerstone of treatment of patients with sepsis. Recent studies have failed to demonstrate a global oxygen debt in patients with sepsis. Furthermore, therapy aimed at increasing systemic oxygen delivery has failed to consistently improve patient outcome. The primary aim of the initial phase of resuscitation is to restore an adequate tissue perfusion pressure. Aggressive volume resuscitation is considered the best initial therapy for the cardiovascular instability of sepsis. Vasoactive agents are required in patients who remain hemodynamically unstable or have evidence of tissue hypoxia after adequate volume resuscitation.