Pancreatic islet transplantation is a promising treatment option for Type 1 diabetes, but organ supply shortage limits its wide adoption. Pig islets are the most promising alternative source and many important measures such as donor animal selection, pig islet production release criteria, preclinical data and zoonosis surveillance prior to human clinical trials have been put forward as a consensus through the efforts of the International Xenotransplantation Association. To bring pig islet transplantation to clinical reality, the development of clinically applicable immunosuppression regimens and methods to minimize immunosuppression to reduce side effects should be established. This review encompasses immune rejection mechanisms in islet xenotransplantation, immunosuppression regimens that have enabled long-term graft survival in pig-to-nonhuman primate experiments and strategies for minimizing immunosuppression in islet xenotransplantation. By thoroughly examining the drugs that are currently available and in development and their individual targets within the immune response, the best strategy for enabling clinical trials of pig islets for Type 1 diabetes will be proposed.