The immunosuppressive regimens currently used in transplantation to prevent allograft destruction by the host's immune system have deleterious side effects and fail to control chronic rejection processes. Induction of donor-specific non-responsiveness (i.e., immunological tolerance) to transplants would solve these problems and would substantially ameliorate patients' quality of life. It has been proposed that bone marrow or hematopoietic stem-cell transplantation, and resulting (mixed) hematopoietic chimerism, lead to immunological tolerance to organs of the same donor. However, a careful analysis of the literature, performed here, clearly establishes that whereas hematopoietic chimerism substantially prolongs allograft survival, it does not systematically prevent chronic rejection. Moreover, the cytotoxic conditioning regimens used to achieve long-term persistence of chimerism are associated with severe side effects that appear incompatible with a routine use in the clinic. Several laboratories recently embarked on different studies to develop alternative strategies to overcome these issues. We discuss here recent advances obtained by combining regulatory T cell infusion with bone-marrow transplantation. In experimental settings, this attractive approach allows development of genuine immunological tolerance to donor tissues using clinically relevant conditioning regimens.