Healing of mucosal damage takes place in two phases: restitution of mucosal integrity and remodeling towards recreating the original glandular arrangements. These processes can be observed in several experimental rodent models: e.g., cryoprobe or NSAID-generated ulcers in the gastric or duodenal mucosa and following surgical resection of the small or large bowel. In some studies, it has been possible to detect changes in the expression of peptides, either in the reparative epithelium or adjacent to the damage, that may contribute to the healing processes. Trefoil peptides are expressed constitutively by epithelial cells in specific regions of the gastrointestinal tract, in association with mucins. Several studies have shown that trefoil peptide expression is enhanced at sites of damage in man and rat, and experimental evidence supports their active participation in the healing process. Recombinant trefoil peptides are able to enhance the rate of epithelial cell migration in vitro and are able to protect against indomethacin-induced damage in vivo, yet they do not depend upon TGF-beta for enhancing cell migration and do not appear to affect acid secretion. The mode of action of trefoil peptides appears to be receptor-mediated but is not simple. There is good evidence that there are interactions between members of the trefoil family and the EGF family that are beneficial for mucosal defense and repair. This raises the possibility that combining trefoil peptides with other growth factors or small molecules may be advantageous for treatment of ulceration.