AbstractTotal lymphoid irradiation (TLI), used in the treatment of some patients with Hodgkin's disease, produces profound immunological changes. In small rodents, mice and rats, a modified version of TLI results in transplantation tolerance for skin and heart allografts. The concept has been expanded to large outbred animals. In baboons transplantation tolerance has been produced for kidney and liver transplantation. The tolerance meets the in vivo and in vitro immunological requirements of durability and specificity. Baboons are currently surviving with normal graft function more than 6 years after kidney transplantation. Kidney‐donor derived skin grafts are accepted permanently, and third‐party skin and kidney grafts are rejected by these tolerant animals. Late chronic rejection occurs in a minority of animals between 6 and 12 months after transplantation. No grafts have been rejected by baboons with normal graft function at 1 year. The most successful protocol in baboons has involved a low cumulative dose (800 cGy), twice a week fractionation regimen of irradiation administered to a wider field than that used in the treatment of Hodgkin's disease. Up to two‐thirds of such animals are rendered tolerant. The role of adjuvant immunosuppressive drug therapy in increasing the tolerant fraction obtained is currently under evaluation. Encouraging results with the use of several methods of TLI in clinical renal transplantation are emerging from 5 centers. The prospect of achieving transplantation tolerance with TLI in the clinical context may be realized with further experience and modification of techniques.