Abstract: Tolerance has been defined as a lack of response to self but a more appropriate definition of tolerance is “any mechanism by which a potentially injurious immune response is prevented, suppressed, or shifted to a noninjurious class of immune response.” Thus, tolerance is related to productive self-recognition, rather than blindness of the immune system to its autocomponents. Oral tolerance, in this sense, is of unique immunologic importance, as it is a continuous natural immunologic event driven by exogenous antigen. Because of their privileged access to the internal milieu, antigens that are continuously in contact with the mucosa are a frontier between foreign and self-components. Thus, oral tolerance is an immunological mechanism that evolved to treat external agents that gain access to the body via a natural route as internal components that then become part of self. Given this, it would seem logical that autoimmune diseases caused by an inappropriate response to self-antigens might ultimately be treated by presenting such autoantigens to the mucosal surface where they can be dealt with in a noninjurous (noninflammatory) immunologic environment. Furthermore, mucosal tolerance as a treatment for autoimmune diseases is an attractive concept, as antigen-specific therapy is the most physiologic means to manipulate immune responses, and mucosal antigen is nontoxic and can be given on a chronic basis. The efficacy of mucosal tolerance has been clearly demonstrated in several animal models.