Given the shortage of human organs for transplantation, the waiting lists are increasing annually and consequently so is the time and deaths during the wait. As most immune suppression therapy is not antigen specific and the risk of infection tends to increase, scientists are looking for new options for immunosuppression or immunotolerance. Tolerance induction would avoid the complications caused by immunosupressive drugs. As such, taking into account the experience with autoimmune diseases, one strategy could be immune modulation-induced changes in T-cell cytokine secretion or antigen therapy; however, most clinical trials have failed. Gene transfer of MHC genes across species may be used to induce tolerance to xenogenic solid organs. Other options are induction of central tolerance by the establishment of mixed chimerism through hematopoietic stem cell transplantation and the induction of ‘operational tolerance’ through immunodeviation involving dendritic or Tregs. I propose that, as the recognition and tolerance of proteins takes place in the thymus, this organ should be the main target for immunotolerance research protocols even as early as during the fetal development.