Rapid rejection of islet allografts is due to both cellular and antibody mechanisms. Isolated islets transplanted intraportally across a major histocompatibility complex (MHC) barrier in rats are rejected in 3–5 days. However, with MHC identity, the median survival time can be as long as 30.5 days. In mice, isolated islets transplanted between H-2-compatible strains survive no more than 1 wk, only a few days more than with an H-2-incompatible cross. In addition, in certain strains of rats and mice, islet isografts from male donors are rejected by female recipients. Fetal pancreases transplanted beneath the kidney capsule (Lewis to Fisher) are rapidly rejected by 4 days, although long-established grafts of fetal pancreas are not vulnerable to rejection in contrast to adult islets. Minimizing histoincompatibility has been unsuccessful in overcoming rejection because of the universal vulnerability of transplanted islets, and attempts to minimize immunogenicity by use of fetal tissue have not prevented rejection; however, culture of donor tissue may prove helpful in reducing immunogenicity. Transplantation of islet tissue into immunologically privileged sites has not resulted in reliable reversal of diabetes. immunosuppression by pharmacologie agents such as cyclophosphamide, azathioprine, and corticosteroids was of minor effectiveness, but antilymphocytic serum was quite effective in rodents, even on xeno-grafts when the injections were continued. Immunologic tolerance produced at birth by donor lymphopoietic cells permits later engraftment of isolated donor islets or whole pancreas. However, enhancement by anti-donor antibody has not been greatly effective in protecting islets against rejection. The possibility that autoimmunity to islet tissue might interfere with the function of transplanted islets was tested in three types of possible autoimmunity: (1) repeated small doses of streptozotocin, (2) encephalomyocarditis virus, and (3) “BB” rats. In all three cases, transplanted islets were effective in reversing experimental diabetes.