Blockade of T-cell costimulatory pathways has proven to be a useful approach in inhibiting allograft rejection and/or inducing tolerance in some experimental models of transplantation, and clinical development of B7 blockade by CTLA4-Ig in kidney transplant recipients is under way. Although calcineurin inhibitors are clinically effective immunosuppressive agents in their own right, conflicting findings have been reported as to whether concomitant use of these drugs with costimulatory blockade has a beneficial or adverse effect on preventing rejection and promoting long-term allograft survival or transplant tolerance. Here, we summarize the current understanding of the interaction between calcineurin inhibitors and T-cell costimulatory blockade strategies in transplantation.