Islet transplantation offers a physiological approach for precise restoration of glucose homeostasis. Recently, the success enhanced by the Edmonton protocol has fostered phenomenal progress in the field of clinical islet transplantation. However, long-term function of the transplanted islets is difficult to maintain. The reasons for islet allograft failure include both nonimmunological (insufficient beta-cell mass and problems related to islet engraftment) and immunological (immune rejection, toxicity of immunosuppressants and autoimmune recurrence) factors. To improve the outcome of islet transplantation, we have focused on solutions to above problems. To preserve transplanted beta cells, we prevent immune rejection in rodent islet xenografts by using microencapsulated islets in combination with an interleukin-1 receptor antagonist (IL1-RA) or 15-deoxyspergualin treatment and inducing tolerance with virus expressing IL1-RA and cytotoxic T lymphocyte-associated antigen (CTLA4)-Ig, as well as protected from autoimmune destruction in NOD mice by using decoy receptor 3 transgenic islets. In addition, we enhance beta-cell function of mouse islet isografts by treating diabetic recipients with exogenous insulin, hyperbaric oxygen, pentoxyphylline, 15-deoxyspergualin, nordihydroguaiaretic acid, cobaltprotoporphyrin, rosiglitazone and vildagliptin. Moreover, in diabetic mice, we are able to expand beta-cell mass of isografts by either transplantation of additional islets or posttransplant exendin-4 treatment. In conclusion, our work demonstrates islet replacement and regeneration approaches are promising for the treatment of type 1 diabetes.