The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death of patients. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools can be used to block the costimulation signals of T-cell activation. Many experimental studies--particularly preclinical studies in nonhuman primates--have focused on blocking the 'classical' B7/CD28 and CD40/CD40L pathways, which are critical in primary T-cell activation. Here, we review the limitations, the recent advances and the first large-scale clinical application of the CTLA4-Ig fusion protein to block the B7/CD28 costimulation pathway. We also focus on new B7/CD28 and tumor necrosis factor (TNF)/TNF-R family costimulatory molecules that can deliver positive or negative costimulation signals regulating the alloimmune response. Strategies that use single agents to block costimulation have often proved to be insufficient. Given the diversity of the different costimulation molecules, future strategies for human transplantation may involve the simultaneous blockade of several selected pathways or the simultaneous use of conventional immunosuppressants.