Dramatic clinical advances indicate that pancreatic islet transplants can reliably restore euglycemia in insulin-dependent patients. However, clinical success actually highlights the pronounced deficiency of allogeneic pancreata available for islet isolation. This pressing issue has revitalized ongoing efforts to develop surrogate donor sources. Xenogeneic donors form a potential alternative tissue source because they can be generated in large numbers and are amenable to genetic engineering. However, there is less understanding of the innate and adaptive immune barriers to islet xenografts relative to those encountered by allografts. Presented evidence indicates that both innate and antigen-specific adaptive immune responses significantly contribute to islet xenograft rejection. Recent evidence suggests that the capacity to induce tolerance to islet xenografts may not differ markedly from strategies used to induce allograft tolerance.