In the second half of the 20th century, the transplantation of replacement organs and tissues to cure disease has become a clinical reality. Success has been achieved as a direct result of progress in understanding the cellular and molecular biology of the immune system. This understanding has led to the development of immunosuppressive pharmaceuticals that are part of nearly every transplantation procedure. All such drugs are toxic to some degree, however, and their chronic use, mandatory in transplantation, predisposes the patient to the development of infection and cancer. In addition, many of them may have deleterious long-term effects on the function of grafts. New immunosuppressive agents are constantly under development, but organ transplantation remains a therapy that requires patients to choose between the risks of their primary illness and its treatment on the one hand, and the risks of life-long systemic immunosuppression on the other. Alternatives to immunosuppression include modulation of donor grafts to reduce immunogenicity, removal of passenger leukocytes, transplantation into immunologically privileged sites like the testis or thymus, encapsulation of tissue, and the induction of a state of immunologic tolerance. It is the last of these alternatives that has, perhaps, the most promise and most generic applicability as a future therapy. Recent reports documenting long-term graft survival in the absence of immunosuppression suggest that tolerance-based therapies may soon become a clinical reality. Of particular interest to our laboratory are transplantation strategies that focus on the induction of donor-specific T-cell unresponsiveness. The basic biology, protocols, experimental outcomes, and clinical implications of tolerance-based transplantation are the focus of this review.