The relationship between Fas-mediated apoptosis and Type 1 diabetes is currently under investigation. Fas/Fas ligand interaction could be involved both in the insulitis process and in beta-cell death. Nevertheless, different mechanisms appear to be involved in human Type 1 diabetes and in NOD mice. In the present work, we review recent evidence of the role of the Fas/Fas ligand system in human and NOD mouse diabetes, describing possible hypotheses for its involvement in the pathogenesis of the disease, with possible implications for therapy and islet transplantation.