Type 1 diabetes is a serious chronic disease with major health risks and heavy burden on patients and society. It is caused by massive immune-mediated loss of insulin-producing beta cells in the pancreas that can so far not be locally corrected. A cellular allotransplant in the liver can install a new beta cell mass but the size is insufficient and the procedure faces limitations of donor shortage, inaccessibility of the implants, risks of associated immunosuppression. Our consortium of research, clinical and bioindustry teams is focused on overcoming these obstacles and implementing a roadmap for translation to preclinical models and clinical trials. We will pursue three interacting tracks. First, our ability to induce beta cell progenitors and stimulate beta cell proliferation in vivo should lead us to cells and compounds that activate this process in a diabetic pancreas, thus activating endogenous beta cell regeneration. Second, we will produce human beta (progenitor) cells in vitro by derivation from stem cells as well as from reprogrammed autologous cells; their therapeutic potential will be compared to that of primary human beta cells following implantation in rodents using a site that is accessible to modulation and monitoring. Third, we will design an antibody-based therapy for inducing immune tolerance to regenerated beta cells and to a beta cell implant. Efficacy, safety and regulatory criteria will be determined for clinical implementation. Clinical protocols will be prepared by adjusting associated therapy and by adopting an accessible and controlled implant site. Clinical trials will benefit from state-of-the art biologic markers for comparative analysis of the developed forms of beta cell therapy. This program should provide proof of principle for strategies that make beta cell transplantation and beta cell regeneration realistic for large numbers of type 1 diabetic patients, and probably also for some categories of type 2 diabetes.