Stress-related mucosal disease develops in patients in the intensive care unit and can result in clinically important bleeding, which is associated with increased mortality. Patients in the intensive care unit without either mechanical ventilation or coagulopathy, which are the primary risk factors for such bleeding, do not seem to need or to benefit from prophylactic acid suppression for stress-related mucosal disease. Although histamine-2-receptor antagonists significantly reduce clinically important bleeding in patients in the intensive care unit and are widely used for prophylaxis, their benefits are limited by the rapid development of tolerance. Previous data suggested that agents that elevate the intragastric pH may increase the susceptibility of patients in the intensive care unit to nosocomial pneumonia. However, the largest study to date showed that intravenous histamine-2-receptor antagonists may not significantly increase the risk of ventilator-associated pneumonia or mortality compared with sucralfate, an agent that does not affect intragastric pH. Intravenous proton pump inhibitors are more potent and longer-acting inhibitors of gastric acid production than intravenous histamine-2-receptor antagonists. The ability of proton pump inhibitors to prevent stress-related mucosal disease and clinically important bleeding seems to be clinically meaningful. Preliminary findings have shown that intermittent administration of intravenous pantoprazole, the first proton pump inhibitor available by this route in the United States, is as effective in raising intragastric pH on the first day as a continuous infusion of a histamine-2-receptor antagonist in clinical trials conducted within an intensive care unit setting. This suggests that for stress ulcer prophylaxis, intermittent dosing with an intravenous proton pump inhibitor may be an alternative to high-dose continuous infusions of a histamine-2-receptor antagonist. These agents must be compared in clinical trials conducted in an intensive care unit setting.