The pig-to-primate model is increasingly being utilized as the final preclinical means of assessing therapeutic strategies aimed at allowing discordant xenotransplantation. We review here the world experience of both pig-to-human and pig-to-nonhuman primate organ transplantation. Eight whole organ transplants using discordant mammalian donors have been carried out in human recipients; only one patient was reported (in 1923) to have survived for longer than 72 hr. Therapeutic approaches in the experimental laboratory setting have included pharmacologic immunosuppression, antibody and/or complement depletion or inhibition, the use of pig organs transgenic for human complement regulatory proteins, and conditioning regimens aimed at inducing a state of tolerance or specific immunologic hyporesponsiveness. The greatest success to date has been obtained with methods that inhibit complement-mediated injury, either by the administration of cobra venom factor or soluble complement receptor I to the recipient (with organ survival up to 6 weeks) or by the use of donor organs transgenic for human decay-accelerating factor (with organ survival up to 2 months). The future of xenotransplantation may lie in the judicious combination of current approaches.