Prophylaxis is routinely provided for critically ill patients admitted to intensive care units (ICUs) who are at high risk for stress-related mucosal damage (SRMD), an erosive process of the gastroduodenum associated with abnormally high physiological demands. Traditionally, treatment options have included sucralfate, antacids and histamine H2 receptor antagonists (H2RAs). The H2RAs are currently the most widely used agents in prophylactic acid suppression; however, proton pump inhibitors (PPIs) have recently replaced H2RAs in the treatment of many acid-related conditions. PPIs achieve a more rapid and sustained increase in gastric pH and are not associated with the rapid tachyphylaxis seen with H2RAs. As a result, and after the introduction of intravenous formulations, PPIs are beginning to be used for the prophylaxis of SRMD in critically ill adults. The high prevalence of renal and hepatic impairment among the ICU population, as well as the need for multiple drug therapy in many patients, means that pharmacokinetic characteristics and the potential for drug interactions may be important considerations in the choice of prophylactic agent. This review seeks to present the pharmacological evidence that may inform decision-making about the prescription of drugs for prophylaxis of SRMD.