Inflammation of the mucosal layer of the gastrointestinal (GI) tract is not only a feature almost always associated with ulceration of those tissues, but it also plays an important role in both the production and healing of the lesions. The mediators that coordinate inflammatory responses also have the capability to alter the resistance of the mucosa to injury induced by noxious substances, while others render the mucosa more susceptible to injury. In this article, we provide a review of the inflammatory mediators that modulate GI mucosal defense. Among the mediators discussed are nitric oxide, the eicosanoids (prostaglandins, leukotrienes, and thromboxanes), neuropeptides, cytokines, and proteinases. Many of these mediators are considered potential therapeutic targets for the treatment of ulcerative diseases of the digestive tract.