The recent success of "steroid-free" immunosuppressive protocols and improvements in islet preparation techniques have proven that pancreatic islet transplantation (PIT) is a valid therapeutic approach for patients with type 1 diabetes. However, there are major obstacles to overcome before PIT can become a routine therapeutic procedure, such as the need for chronic immunosuppression, the loss of functional islet mass after transplantation requiring multiple islet infusion to achieve euglycemia without exogenous administration of insulin, and the shortage of human tissue for transplantation. With reference to the first obstacle, stable islet allograft function without immunosuppressive therapy has been achieved after tolerance was induced in diabetic primates. With reference to the second obstacle, different strategies, including gene transfer of antiapoptotic genes, have been used to protect isolated islets before and after transplantation. With reference to the third obstacle, pigs are an attractive islet source because they breed rapidly, there is a long history of porcine insulin use in humans, and there is the potential for genetic engineering. To accomplish islet transplantation, experimental opportunities must be balanced by complementary characteristics of basic mouse and rat models and preclinical large animal models. Well-designed preclinical studies in primates can provide the quality of information required to translate islet transplant research safely into clinical transplantation.