Xenotransplantation, involving the transplantation of pig organs into humans, would resolve the current shortage of organs. It involves, however, a new therapeutic approach to organ transplantation. The presence of natural antibody 'in primates directed against Galα1,3Gal epitopes on pig vascular endothelium leads to early antibody-mediated rejection. An elicited antibody response against the same target epitopes as well as against nonGal antigens intensifies the immune destruction of the organ. Even the minimal deposition of antibody appears to lead to the development of a consumptive coagulopathy that can be fatal. Approaches being investigated to overcome these barriers include depletion and inhibition of natural antibody and complement, and suppression of the elicited T cell-dependent antibody and cellular responses. In addition, however, physiologic incompatibilities between human and pig, particularly those relating to coagulation, may enhance or complicate the immune process, and may require additional therapeutic measures. Current approaches aimed at achieving successful xenotransplantation also include investigation of agents that prevent potential xenozoonotic infection of the recipient. At present, therefore, the therapeutic interventions required to attempt to overcome the barriers to xenotransplantation are multiple. Work indicating progress in the breeding of pigs that do not express the critical Galα1,3Gal epitopes, however, is encouraging. The introduction of these pigs may greatly reduce the therapy required, and may ultimately allow the development of methods to induce tolerance to the transplanted pig organ.