The most intensively studied autoimmune disorder, type 1 diabetes mellitus (DM1), has attracted perhaps the greatest interest for gene-based therapeutic and prophylactic interventions. The final clinical manifestation of this immunologically and genetically complex disease, the absence of insulin, is the major starting point for almost all the gene therapy modalities attempted to date. Insulin replacement by transplantation of islets of Langerhans or surrogate beta cells is the obvious choice, but the allogeneic nature of the transplants activates potent antidonor immunoreactivity necessitating gene and cell-based immunosuppressive strategies as an alternative to the toxic pharmacologic immunosuppressives indicated for classic solid organ transplants. Accumulating knowledge of the cellular mechanisms involved in onset, however, have yielded promising tolerance induction prophylactic approaches using genes and cells. Despite the early successes in a number of animal models, the true test of efficacy in humans remains to be demonstrated.