Aspiration of oropharyngeal and gastric contents during surgery, although infrequent, is a recognized complication of general anesthesia that carries significant risk for serious complications. Complications of aspiration have been reported to cause 10% to 30% of anesthesia-related deaths. Unconsciousness interferes with multiple biologic mechanisms that guard the airway against aspiration, and this is compounded in surgery by anesthesia-induced neurologic impairment and the risks related to placement of nasogastric and endotracheal tubes. Consequences of anesthesia-related aspiration include aspiration pneumonia, acute respiratory distress syndrome, pulmonary edema, and long-term complications such as laryngotracheal damage and decreased lung compliance. Therefore, averting aspiration, particularly in the elderly and other high-risk patients, should be part of the perioperative plan. Although antacids and histamine 2-receptor antagonists have been used perioperatively with some success, they are limited by short duration of action and systemic side effects, among other factors. Proton pump inhibitors are currently being investigated in surgical patients at risk for aspiration or stress ulcers and seem to be potent, extremely effective, and well tolerated. This article reviews the risks for, and potential outcomes of, anesthesia-related aspiration, identifies high-risk populations, and outlines the experience to date with available preventive treatments.