T cell-mediated mechanisms of xenograft rejection appear resistant to standard immunosuppression protocols used to prevent allograft rejection and, consequently, higher doses of immunosuppressive drugs are required to promote xenograft compared to allograft survival. Evidence from recent studies suggests that porcine xenografts may be especially immunogenic in humans because of a prominent and vigorous indirect xenoresponse and because of the ability of porcine endothelium to activate human T cells. This has led to an anxiety that systemic immunosuppressives, used as the mainstay of therapy for clinical xenotransplantation, may not allow the long-term survival of porcine organs transplanted into human recipients. This article will review the biology of T cell xenoresponses, present the case for the development of novel graft-specific immunosuppressive regimes in clinical xenotransplantation, and review recent experimental progress in this area.