Strategies for restoration of beta cell mass will fall under either "replacement" (transplantation of insulin producing cells), "differentiation/reprogramming" (generation of insulin producing cells from native non-insulin-producing cells), "regeneration" or "expansion" of residual beta cell mass (e.g., from endogenous precursors/stem cells or by beta cell expansion in micro-secretors). A multicenter Phase III trial of transplantation of adult pancreatic islet has been recently completed and is moving towards a Biological License Application (BLA) in the USA, while novel technologies to engineer an intra-abdominal mini-endocrine pancreas are currently being tested in pilot clinical trials. Novel immunotherapy technologies will be explored for restoration of self-tolerance or to block the alloimmune destruction of the new insulin producing cells, independently from the technology used for restoration of beta cell mass, such as regeneration, reprogramming or replacement (e.g., transplantation of pancreatic islets or stem cell derived insulin producing cells). Abrogation of autoimmunity and alloimmunity, or their effects, could be achieved by either tolerance induction strategies or immune protection (e.g., engineered microenvironment or selective permeability physical barriers like those introduced by micro-, conformal- or nano-encapsulation). Any future therapeutic technology considered must avoid side effects such as those associated with life-long immunosuppression, currently limiting the indications of adult islet transplantation to the most severe cases of T1DM. There is a broad consensus on the idea that stem cells will eventually replace adult pancreatic islets in the future. However, the jury is still out regarding the candidate cell type/s and approach that will ultimately succeed. Differentiation technologies for generation of insulin-producing cell from adult stem cells will be further developed, spanning from signal-driven approaches, to genetic manipulation and even strategies of in-vivo maturation after systemic administration. The more suitable alternatives between replacement, reprogramming and regeneration strategies will be further developed in pre-clinical model systems and tested in pilot clinical trials, while carefully assessing safety, efficacy, cost-effectiveness and the relative potential for scale up, to offer a realistic therapeutic option for most patients affected by diabetes.