The human gut offers more than 200 m2 of mucosal surface, where direct interactions between the immune system and foreign antigens take place to eliminate pathogens or induce immune tolerance toward food antigens or normal gut flora. Therefore, mucosally administered antigens can induce tolerance under certain circumstances. In autoimmune diabetes, mucosal vaccination with autoantigens elicits some efficacy in restoring tolerance in mice, but it never succeeded in humans. Furthermore, in some instances autoimmunity can be precipitated upon oral or intranasal autoantigen administration. Therefore, it is difficult to predict the effect of mucosal vaccination on autoimmunity and much effort should be put into establishing better assays to reduce the risk for possible adverse events in humans and enable a rapid and smooth translation.