To date, the only successful means of achieving allogeneic transplantation tolerance in the clinic has involved induction of mixed lymphohematopoietic chimerism. Such chimerism was first achieved in mice and subsequently in large animals, including miniature swine, monkeys and most recently humans. The mechanism of tolerance has differed between models, involving both deletional and regulatory mechanisms, in varying proportions, depending on the model. Considerable progress has also been made toward induction of tolerance across the xenogeneic pig-to-primate barrier, although complete success has not yet been achieved. The two approaches toward xenograft tolerance currently being investigated both involve establishment of a mixture of host and donor cells in the thymus, in one case through administration of donor bone marrow to the recipient and in the other through vascularized donor thymus transplantation to a thymectomized recipient. Hopefully, a combination of these approaches may provide an effective means for achieving full tolerance and thereby bringing xenograft organ transplantation to the clinic.