Prostaglandins protect the gastroduodenal mucosa from damage caused by diverse noxious agents. This protection (cytoprotection) occurs under experimental conditions where intraluminal acid is required for maximal expression of damage (e.g., stress, aspirin, and bile acids), as well as where damage occurs irrespective of the presence of acid (e.g., 100% ethanol, boiling water, and lye). Prostaglandins stimulate several factors felt to be important in maintaining normal mucosal integrity, such as mucus synthesis and secretion, mucosal bicarbonate secretion, mucosal blood flow, and cellular repair. Inhibition of the prostaglandin synthetic enzyme, cyclooxygenase, by nonsteroidal anti-inflammatory drugs (NSAIDs), is associated with increased gastroduodenal mucosal damage and ulceration. This damage is primarily the result of decreased tissue levels of prostaglandins, but may also be due to direct NSAID actions on the mucosa, as well as with shifting of arachidonic acid metabolism from synthesizing protective prostaglandins to increased production of injurious leukotrienes. There is also evidence that patients with peptic ulcer disease have a deficiency of gastroduodenal mucosal prostaglandin synthesis, so that prostaglandins may play a pathophysiologic role in this disorder. Prostaglandins have a unique ability to prevent NSAID-induced gastric damage in humans, and also appear to improve ulcer healing during the continuation of NSAID therapy.