Organ transplantation has become an accepted and successful therapeutic intervention for many patients with end–stage organ disease. Current conventional immunosuppressive regimens achieve very good short–term allograft survival but long–term outcomes are less than adequate. Furthermore, non–specific immunosuppression has its attendant side–effects including increased risks of malignancy and infection as well as drug–specific sequellae. With recent advances in the field of immunology, promising new therapies have arisen that could potentially eliminate lifelong drug therapy and promote indefinite acceptance of the donor tissue. Identification of co–stimulatory signals essential for T–cell activation has provided exciting new possibilities for controlling the alloimmune response. The compatibility of these new agents with proven conventional therapeutics has yielded mixed results. When used in combination, their immunosuppressive properties appear synergistic. However, if the goal of therapy is sustained, specific T–cell hyporesponsiveness, many conventional agents antagonize the effects of co–stimulatory blockade in several immune tolerance models.