The basic science immunology community is quite accepting of the phenomenon of oral tolerance induction in animals; however, in contradistinction, the clinical community is somewhat agnostic regarding oral tolerance. Progress in multiple sclerosis has not been definitive and outcomes in RA have been modest at best. Recent reports in animal models have suggested that oral ingestion of autoantigen can have deleterious effects on the host. Although those experiments have had a highly artificial framework, they are consistent with the possibility that oral antigen therapy in human disease may be: (1) beneficial; (2) of no consequence; or (3) detrimental. An extremely open mind will hopefully be applied to future research efforts.