Today, liver transplantation is the treatment of choice for most of the patients with endstage liver failure. Nevertheless, immunosuppressive regimens are not yet optimal; rejection still represents the first cause of graft loss, and infections and malignancies related to the non specific immunosuppression are a major source of morbidity and mortality. Therefore, the development of protocols aiming to induce transplantation tolerance--the survival of the graft without immunosuppression--represents a crucial challenge for the future. In the present report, we discuss two different approaches in this perspective. First, as compared with other organ, liver graft may present a particular propension to induce chimerism. As this phenomenon could promote allograft survival, the enhancement of chimerism by administration of donor cells, simultaneously with the transplantation, may constitute a new therapeutic strategy to induce tolerance. Second, experimental observations indicate that the initiation of the immune reaction in the liver may preferentially induce a TH2-type response. As TH2 lymphocytes are poor effector of acute rejection, this phenomenon could contribute to the spontaneous survival of liver graft and their tolerogenic effect observed under some experimental conditions. However, the capacity of TH2 cells to induce lymphoproliferative disease and their possible role in chronic rejection will probably represent a major limitation for clinical use of this strategy.