Mixed allogeneic chimerism is currently being investigated as a means to induce donor-specific transplantation tolerance across MHC barriers. Here, Megan Sykes and David Sachs compare the two most extensively studied examples-lethal whole body irradiation followed by reconstitution with mixed allogeneic and syngeneic marrow, and total lymphoid irradiation followed by allogeneic marrow infusion-and assess the likelihood that they will be clinically useful in the future. r~,~,.,;,......,~ A......." immunosuppressive*~...... the development of safe methods for achieving donorspecific tolerance across major histocompatibility complex (MHC) barriers remains a major goal of research in transplantation immunology. Although lethal irradiation followed by reconstitution with allogeneic bone marrow leads to fully allogeneic chimerism and successful induction of specific transplantation tolerance in animal models 1, two major risks associated with such treatment have limited its applicability to clinical transplantation. The first risk, graft-versus-host disease (GVHD), can be substantially reduced or eliminated by T-cell depletion of donor marrow, although such treatment has been associated in man and animals with a high incidence of failure of marrow engraftment 2.3. The second risk, of reduced long-term immunocompetence, is probably due to the failure of donor-derived antigen-presenting cells to cooperate with lymphoid cells which are restricted by host MHC antigens 4. In most clinical organ transplant situations, these risks generally outweigh those associated with long-term nonspecific immunosuppression. Mixed allogeneic chimerism provides an alternative approach to the induction of donor-specific transplantation tolerance which offers several practical and theor-