The inability to provide an adequate supply of human organs for clinical transplantation has created a strong interest in the use of nonhuman, especially nonprimate, organs. The first biological obstacle confronting such discordant transplantations is a series of violent reactions that result in hyperacute rejection of the xenograft. Significant advances in controlling hyperacute rejection have been achieved recently through the generation of transgenic pig donors bearing human complement regulatory proteins. However, when hyperacute rejection is averted, the xenografts are rejected in 2-70 days in spite of high-dose immunosuppression, by a process collectively termed delayed xenograft rejection. Delayed xenograft rejection is characterized by a refractoriness to conventional immunosuppression, extensive xenoreactive antibody deposition, and cellular infiltration that is dominated by macrophages. We have examined the features of extended host and graft response in the concordant hamster-to-rat xenotransplant model, where such features have historically been obscured by early graft destruction. Hamster hearts transplanted into rats do not encounter hyperacute rejection but are rejected within 3-4 days when xenoreactive antibody titers rise exponentially to levels that elicit a classical antibody- and complement-mediated acute xenograft rejection. We have successfully blocked acute xenograft rejection by a combination of immunosuppressive agents, leflunomide, and cyclosporine. Stopping the immunosuppression resulted in graft rejection that is histologically characterized by extensive xenoreactive antibody deposition and cellular infiltration that is predominantly composed of macrophages. We have noted the similarities between the histopathology of rejection of long-surviving concordant xenografts and that described for discordant xenografts and refer to the process of rejection of concordant grafts that have escaped acute xenograft rejection, delayed xenograft rejection.