The biological validation of islet grafts would free total pancreas resection from the onus of severe diabetes mellitus. Islet cell transplants can reverse diabetes mellitus and prevent complications in animal models. Immune rejection has foiled attempts at human transplantation despite moderate success with whole pancreas grafts. Aggressive rejection of islet grafts has been extensively studied in animal models and seems no different in substance from standard cell-mediated rejection but vastly different in tenacity. Rejection cannot be prevented by immunosuppression strategies effective for transplantation of heart, kidney, or liver. New strategies to circumvent islet rejection include encapsulation of the islets to obfuscate immune recognition, pretreatment of the islets in vitro to reduce immunogenicity, donor manipulation to provide specific tolerance, and combination strategies. In the development of these strategies, much has been learned or confirmed about the nature of immune rejection, and another round of human trials can be anticipated.