Radioimmunotherapy (RIT) combines the advantages of specific immunotherapy with the cytotoxicity of radionuclides resulting in targeted radiation therapy. In the setting of allogeneic hematopoietic cell transplantation (HCT), RIT can be used to both target tumor cells and to suppress immunocompetent recipient cells. RIT with beta-emitters has been successfully used for further dose intensification of myeloablative conditioning regimens for HCT. Alpha-emitters with their short path length and high linear energy transfer bear certain advantages over beta-emitters if used to target hematopoietic cells. Using a canine model of non-myeloablative HCT, one could demonstrate that pre-transplant RIT with the alpha-emitter bismuth-213 (213Bi) coupled to anti-CD45 or anti-TCRalphabeta monoclonal antibodies (mAb) together with post-grafting immunosuppression with mycophenolate mofetil and cyclosporine can achieve stable engraftment and long-term mixed chimerism. The two mAbs may allow a tailored approach to RIT in non-myeloablative conditioning with 213Bi-anti-CD45 used for patients with hematologic malignancies and 213Bi-anti-TCRalphabeta for non-malignant diseases. Extensive studies of biodistribution, dose de-escalation and toxicity provide the basis for the conception of clinical trials using RIT for non-myeloablative HCT.