Achieving immunological tolerance is an important goal in the effort to reduce long-term morbidity and mortality in organ transplant recipients. The establishment of mixed chimerism through the transplantation of donor bone marrow cells is an experimental approach for tolerance induction with clinical potential. Permanent, robust donor-specific tolerance has been reliably achieved in various animals models of mixed chimerism. This article reviews the historical background and the progress achieved in recent years in developing mixed chimerism protocols in rodents, large animals and also regards the issue of clinical applications.