Stress-related mucosal disease (SRMD) includes stress-related injury (superficial mucosal damage) and stress ulcers (focal deep mucosal damage). Both types are caused by mucosal ischemia, and both show a propensity for the acid-producing corpus and fundus. Prophylaxis of stress ulcers may reduce major bleeding but, so far, has not been shown to improve survival. The most widely used drugs for stress-related injury are the intravenous histamine H(2)-receptor antagonists. Proton pump inhibitors (PPIs) are the most potent acid-suppressive pharmacologic agents. The available PPIs significantly increase gastric pH for up to 24 hours after one dose. Tolerance does not develop, and adverse effects are few. Preliminary studies have demonstrated a significant reduction in SRMD bleeding for patients receiving PPI prophylaxis. PPIs may become an effective tool for reducing the incidence of SRMD in critically ill patients.