The ability to induce tolerance to alloantigens, and in the future xenoantigens, in vivo is essential to progress in transplantation. The immunosuppressive drugs available for use in clinical transplantation at present are capable of preventing or reducing the incidence of acute rejection in the first few months after transplantation, but they appear less effective at preventing chronic graft loss. The induction of tolerance to the histocompatibility antigens of the organ donor in the long term after transplantation would eliminate the need for long-term administration of these nonspecific immunosuppressive drugs. This alone would have a major impact on the quality of life of patients with long-term surviving organ grafts by reducing the immunologic and nonimmunologic complications associated with long-term immunosuppressive therapy. The strategies for the induction of tolerance in the long term after transplantation, and more ambitiously before transplantation, that are currently being explored in a variety of experimental models are the subject of this review.