The induction of donor-specific unresponsiveness constitutes the most desirable means of securing long-term graft survival, as it would spare the recipient from the deleterious effects of global immunosuppression. Based on recent insights into the factors controlling both intrathymic and extrathymic clonal deletion or inactivation of T cells, this objective can potentially be accomplished by the direct inoculation of the thymus with alloantigen to modulate T cell development at both the thymic and post-thymic level.