Numerous agents increase gastric mucosal resistance against intraluminal ulcerogens. Although the precise mechanisms of gastroprotection are uncertain, various endogenous mediators involved in gastroprotective effects have been characterized. As prostaglandins exert potent protective effects and inhibition of prostaglandin formation abolishes "adaptive gastroprotection," they have been proposed as key mediators in mucosal defense. This paper reviews the role of endogenous prostaglandins showing striking differences between different forms of gastroprotection. Thus, whereas the protective effect of the antiulcer drug rebamipide involves prostaglandins as essential mediators, the protection conferred by the antacid hydrotalcit is prostaglandin-independent. Furthermore, gastroprotection can occur even when mucosal prostaglandin generation is suppressed. This phenomenon has been observed with some nonsteroidal antiinflammatory drugs, agents that modulate sulfhydryls and certain metals. Recent data suggest that both cyclooxygenase-1- and cyclooxygenase-2-derived prostaglandins can increase mucosal resistance. The precise role of constitutive and inducible forms of cyclooxygenase in gastroprotection, however, remains to be established.