The intestinal immune system discriminates between potentially harmful and harmless foreign proteins. The basis for this differential response may be related to the conditions of antigen presentation by antigen-presenting cells, as determined by their phenotype or activation state. How these conditions affect specific immunologic unresponsiveness to later challenge with an antigen is not known. Two possible mechanisms are the induction of anergy or deletion of responsive cells and the activation of regulatory cells or mediators, and the mechanism may very depending on the tolerizing regimen used. Should regulatory cells be involved, they are speculated to induce tolerance through their production of inhibitory cytokines, such as IL-4, IL-10, and TGF-beta. Studies using specific antibodies and selective genetic knockout (KO) strains of mice, however, have provided conflicting data. A final intriguing possibility is that tolerance results from cognate interactions between T cells and APCs, so that tolerant T cells or APCs prime T cells they contact to deliver a tolerogenic signal to the next T cell they encounter, possibly through a function dependent on interactions between Notch family receptors and their ligands. As with many questions in mucosal immunology, definition of the mechanisms of oral tolerance (OT) has proved difficult to address experimentally, but promising approaches include study of the distribution of fed antigen, of targeted genetic KOs, and of transgenic strains.