Administration of autoantigens, especially via the mucosal route, can induce tolerance under certain circumstances. In autoimmune diabetes, mucosal vaccination with autoantigens was frequently effective in restoring tolerance in mice but has not yet succeeded in humans. Furthermore, in some instances, autoimmunity can be precipitated upon autoantigen administration. We will here briefly discuss the underlying reasons and delineate which efforts should be made in the future to rationally translate antigen-specific immunotherapy, for example, by establishing better assays to reduce the risk for possible adverse events in humans.