The induction of tolerance for allografts, obviating the need for immunosuppression, is the ultimate goal in transplantation. Immunoregulatory antibodies preventing graft rejection are promising candidates for the induction of tolerance. Costimulation blockade could be a useful approach to inducing donor-specific nonresponsiveness in organ transplantation. Rodent studies and in vitro studies using human or nonhuman primate peripheral blood mononuclear cells indicated that this approach might indeed lead to specific T-cell anergy. Nonhuman primate studies, in which the B7 costimulation pathway was blocked, have so far not led to permanent drug-free graft acceptance. The results are promising, however, because during the treatment period with B7 costimulation blockade alone or combined with anti-CD40 or cyclosporine, no graft loss was observed and donor-specific antibody formation was prevented. Based on these findings, new approaches to inducing drug-free graft acceptance should be investigated.