The gastrointestinal epithelium produces a wide variety of peptides which may contribute to protection from injury as well as repair after injury occurs. Restitution, the initial phase of mucosal repair, is accomplished by rapid migration of the epithelium to re-establish surface epithelial continuity. A wide variety of growth factors and cytokines, which are produced both by the epithelium itself and by lamina propria cell populations, promote restitution in models of epithelial injury. These include members of the epidermal growth factor (EGF)/transforming growth factor (TGF)alpha, and the fibroblast growth factor (FGF) families, as well as a variety of cytokines (interleukin [IL]-1, IL-2, IL-4, IL-15, and interferon gamma) which interact with their cognate receptors on the intestinal epithelial basolateral surface. These growth factors and cytokines appear to promote restitution through a TGF beta-dependent pathway and act to both enhance expression of TGF beta and to entrance its bioactivation. In contrast, trefoil peptides, members of a recently recognized family of small proteins produced by goblet cells, both protect the epithelium and promote restitution following secretion onto the apical surface through mechanisms distinct from those peptides acting through TGF beta. Thus, rapid repair after epithelial injury is achieved through complementary mechanisms acting at the basolateral and apical surfaces of the epithelium.