Although the incidence of bleeding from stress ulceration has declined over the last two decades, this condition remains of both clinical and economic importance. Recent studies suggest that stress ulcer prophylaxis is only indicated in high-risk patients, most notably those patients undergoing mechanical ventilation and patients with a coagulopathy. There is little evidence that antacids, sucralfate, and H2 blockers differ with respect to the prevention of clinically important bleeding. The choice of agents is therefore largely determined by economic factors and the risk of drug-associated complications.