OBJECTIVE A review is presented of the evidence behind the current use of therapies for the prevention of stress-related mucosal disease and bleeding in the nonintensive care unit (ICU), general medicine population. CONCLUSIONS The use of proton pump inhibitors and histamine H2-receptor antagonists for the prevention of stress ulcers has been well-defined in critical care patients. In 1999, the American Society of Health-System Pharmacists (ASHP) published guidelines on the use of stress ulcer prophylaxis in medical, surgical, respiratory, and pediatric ICU patients. In recent years, the practice of stress ulcer prophylaxis has become increasingly more common in general medicine patients, with little to no evidence to support it. Multiple risk factors have been identified for the development of stress ulcers, such as major trauma, severe head injury, multiple organ failure, burns covering more than 25-30% of the body, and major surgical procedures. Multiple studies have demonstrated the overuse of acid-suppressive therapy (AST), with as many as 71% of patients admitted to the hospital receiving some form of treatment. While many practitioners view AST to be harmless, its use is not without risks. Subsequently, a significant number of patients are discharged home on these medications, increasing economic cost and potentially increasing the risk of pneumonia or Clostridium difficile-associated disease. CONCLUSIONS AST is commonly misused in hospitals, with as many as 71% of patients in general medicine wards receiving some sort of AST without an appropriate indication. Anticoagulant therapy has been identified as a risk factor for GI bleeding in hospitalized patients, but prophylaxis with AST has not been found to lower that risk. Although PPIs, H2-antagonists, and antacids are often viewed as safe, patients--particularly those with complicated disease states and complex drug regimens--should not be unduly exposed to the adverse effects and drug interactions associated with those agents. Many such patients treated with the drugs while hospitalized continue to receive AST as outpatients. The cost of inappropriate stress ulcer prophylaxis in medicine patients was found in one trial to exceed $111,000 for one year. The use of AST for the prevention of stress ulcers in general medicine patients is currently not recommended or supported in the clinical literature.