Two major factors currently limiting the field of transplantation are (1) treatment-related complications and (2) donor organ availability. This article reviews progress from our laboratory in research directed at solutions to both of these limitations. The induction of specific tolerance could eliminate many of the treatment-related complications currently attributable to nonspecific immunosuppressive drug therapy. The methodology being investigated involves use of mixed chimerism as an approach to transplantation tolerance. In this case, the presence of certain donor bone marrow-derived elements induces specific tolerance, whereas host-type antigen presenting cells confer normal immunocompetence. In addition, extension of this work toward tolerance across xenogeneic barriers could eliminate the limitation of organ donor availability. A nonmyeloablative preparative regimen capable of inducing mixed chimerism and tolerance has previously been described from our laboratory for both allogeneic murine systems and concordant xenogeneic rat-->mouse systems. Current studies attempting to extend this regimen to a discordant pig-->monkey xenograft model are reviewed. If successful, these studies could provide a virtually limitless source of xenogeneic donor organs.