Stress-related mucosal disease is common in critically ill patients and can result in significant morbidity. The pathophysiology of this condition is multifactorial but mucosal ischaemia and gastric acid have pivotal roles. The major risk factors for developing stress-related mucosal bleeding are prolonged mechanical ventilation and coagulopathy. The mainstay of clinical management is prevention with acid-suppressing medications and cytoprotective agents. This chapter discusses medications used to prevent this condition and suggests an approach for management. Recent developments in gastroenterology include the development and use of proton pump inhibitors and the discovery of the association Helicobacter pylori with gastritis. The role of each of these in stress-related mucosal disease is discussed. Finally, an approach to the bleeding critically ill patient is presented.