Gastric ulcers have been known to develop in critically ill patients secondary to physiological stress since the 19th century. It is only relatively recently that stress ulcer prophylaxis has become an established routine practice in the intensive care unit. Numerous terms have been used to describe stress ulcers, but stress-related mucosal disease (SRMD) is commonly used. Significant morbidity and mortality in critically ill patients is caused by SRMD and related bleedings, but the incidence depends on the definition of bleeding. Pathophysiology of SRMD is multifactorial and involves a complex set of interactions that causes a breakdown of mucosal proactive defenses, leading to ulceration. Critically ill patients are at an increased risk for developing SRMD and subsequent bleeding secondary to several risk factors. To minimize stress-related mucosal bleeding, several regimens have been used. This article presents an update on the incidence, pathophysiology, risk factors, and prophylaxis of SRMD.