The results of trials in which autoantigens have been fed to individuals affected by autoimmune diseases - multiple sclerosis, rheumatoid arthritis and type 1 diabetes - have been disappointing in terms of clinical improvement. This is in striking contrast to the results in experimental rodent models of these diseases. The outcome of the recent DPT-1 trial testing oral insulin in individuals at risk of type 1 diabetes was also disappointing, in contrast to the effects of oral insulin in the non-obese diabetic (NOD) mouse model of type 1 diabetes. However, it is premature to conclude that mucosal tolerance works only in in-bred rodents and not in humans with autoimmune disease. Except for oral insulin in DPT-1, the human trials were performed in individuals with end-stage disease when this form of immune regulation might not be expected to be effective. Importantly, in no trial was an immune response to the autoantigen documented, to demonstrate that the dose was at least bioavailable. Furthermore, mucosal autoantigen administration is a ‘double-edged sword’ and in rodents can lead not only to regulatory and protective immunity but also to pathogenic, tissue-destructive immunity and exacerbation of autoimmune disease. When suppression of autoimmune disease is observed it may be because autoantigen was administered under conditions which minimize induction of pathogenic immunity. Thus, clinical protocols for mucosal autoantigen administration may need to be modified to favor induction of regulatory immunity. In this short review, we discuss recent studies in autoimmune diabetes-prone NOD mice indicating that with novel modifications mucosal autoantigen administration could be harnessed to prevent type 1 diabetes in humans.