Oral tolerance refers to the oral administration of protein antigens, which induces a state of systemic nonresponsiveness specific for the fed antigen. This method of inducing immune non-responsiveness has been applied to the prevention and treatment of experimental animal models of autoimmune disease. Extensive research in this area over the past ten years has led to the conclusion that two mechanisms are operative in the mediation of oral tolerance--active suppression and clonal anergy/deletion. A number of factors have been identified that determine which mechanism of tolerance is operative--antigen dose, antigen form, and the timing of antigen administration. Work from these animal models has recently been extended into human clinical trials of multiple sclerosis, rheumatoid arthritis, diabetes, uveitis, and allergy, with differing degrees of success. In this review, a discussion is provided of the animal model systems where oral tolerance has been applied and the clinical trials where an oral tolerization approach has been attempted. Moreover, recent mechanistic studies are reviewed and a model proposed for the induction of oral tolerance.