Key elements of the current approach to treating sepsis are reviewed, and examples are given to illustrate the difficulty of designing and evaluating trials in sepsis. A patient with sepsis is likely to have symptoms characteristic of the systemic inflammatory response syndrome. Initially, ruling out noninfective causes, locating the site of infection, and obtaining cultures before beginning antimicrobial therapy are critical. Aggressive fluid resuscitation and hemodynamic support are used to restore tissue perfusion and normalize cellular metabolism. Vasopressor therapy with dopamine or norepinephrine is needed in patients unresponsive to fluid resuscitation. Dobutamine should be administered in patients whose cardiac output is inadequate despite optimization of fluids and pressors. Supportive care includes deep vein thrombosis prophylaxis, nutrition support, stress ulcer prophylaxis, and management of acute lung injury. Attempts to modify the sepsis response and improve the outcome in these patients have yielded limited benefits. Recent small studies have shown benefits with low-dose hydrocortisone in patients with refractory sepsis. One challenge in study design is that a therapy may target a subset of patients that cannot be identified at the outset. Management of patients with suspected or documented sepsis focuses on hemodynamic support, appropriate antimicrobial therapy, and other supportive care.