Similar to in the upper gastrointestinal tract, prostaglandins represent one of the most important components of mucosal defense in the small intestine and colon. The effects of prostaglandins in this context are widespread, ranging from maintenance of blood flow to stimulation of mucus secretion to modulation of the mucosal immune system. There is little doubt that the ability of NSAIDs to cause injury throughout the gastrointestinal tract and to exacerbate IBD is due in large part to the ability of these agents to suppress prostaglandin synthesis. With the advent of selective COX-2 inhibitors, it has become possible to dissect further the roles of prostaglandins in mucosal defense. The weight of evidence collected so far suggests that prostaglandins derived from COX-2 are important in promoting the healing of mucosal injury, in protecting against bacterial invasion, and in down-regulating the mucosal immune system. Suppression of COX-2 in a setting of gastrointestinal inflammation and ulceration has been shown in experimental models to result in impairment of healing and exacerbation of inflammation-mediated injury. In the near future, pharmacologic probes will be available that will permit clinicians to identify better the specific prostaglandin receptors that mediate the effects of this group of mediators on the various aspects of mucosal defense. This identification should permit the development of therapeutic agents that specifically can modulate some aspects of mucosal defense without having undesired effects on other aspects of mucosal function. Such agents may permit clinicians to enhance mucosal repair selectively and to block selectively any contribution of prostaglandins to the pain associated with IBD.