The ultimate goal in transplantation is modulation of the immune response to produce tolerance without immunosuppression. To date only a state of pseudotolerance for the allograft has been achieved through the use of potent pharmacologic and biologic manipulations. Despite these manipulations to prevent acute rejection, chronic rejection eventually results in graft failure. Thus, different strategies have been sought to induce tolerance and prevent acute and chronic rejection. Historically, donor-specific transfusion (DST) was one such strategy attempted. Donor-specific transfusion has been used primarily in living donor organ transplantation. With the concern that DST may sensitize patients, thereby preventing transplantation and introduction of cyclosporine, the use of DST was curtailed. More recently, donor bone marrow (DBM) infusion at the time of cadaveric transplantation has been used to facilitate development of microchimerism and tolerance to abrogate acute and chronic rejection. However, DBM infusion may predispose the recipient to graft-versus-host disease and is not easily accomplished in living donor organ transplantation. The potentially immunomodulating and tolerizing mechanisms of DST and DBM infusion are similar and include induction of anergy, stimulation of anti-anti-HLA antibodies, provision of soluble HLA antigen, suppressor cell and/or veto cell activity, clonal deletion, regulation of cell surface molecules, regulation of cytokines, promotion of microchimerism, or a combination of these. Of these mechanisms, microchimerism with the concomitant persistence of soluble donor HLA antigen is felt by many to be the most important. Although microchimerism is detectable in many patients who are tolerant of their grafts, there is no clear evidence that chimerism is responsible for the induction or maintenance of tolerance.