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The induction of donor-specific tolerance remains an important objective in transplantation to obviate the need for immunosuppression and prevent chronic rejection. Operational tolerance to cardiac allografts can certainly be induced in small animal models. Recent interest has focused on refining the tolerance induction regimens to minimize toxicity and on examining the mechanisms responsible for donor-specific unresponsiveness in these experimental systems. Particular progress has been made on strategies to block T-cell costimulation and on delivery of alloantigens via donor-specific transfusion or bone marrow infusion. Interactions between various forms of immunotherapy and conventional immunosuppression are being studied and there is early evidence of synergy, as well as data suggesting inhibition of tolerance induction by calcineurin inhibitors.