The therapeutic potential of bone marrow-derived human mesenchymal stem cells (hMSC) has recently been brought into the spotlight of many fields of research. One possible application of the approach is the repair of injured tissues arising from side effects of radiation treatments and accidents. The first challenge in cell therapy is to assess the quality of the cell and the ability to retain their differentiation potential during the expansion process. Efficient delivery to the sites of intended action is also necessary. We addressed both questions using hMSC cultured and then infused to Non Obese Diabetes/Severe Combined Immunodeficiency (NOD/SCID) mice submitted to total body irradiation. Further, we tested the impact of additional local irradiation superimposed to total body irradiation (TBI), as a model of accidental irradiation. Our results showed that the hMSC used for transplant have been expanded without significant loss in their differentiation capacities. After transplantation into adult unconditioned mice, hMSC not only migrate in bone marrow but also into other tissues. Total body irradiation increased hMSC implantation in bone marrow and muscle and further led to engraftment in brain, heart, and liver. Local irradiation, in addition to TBI, increased both specific homing of injected cells to the injured tissues and to other tissues outside the local irradiation field. MSC may participate to restoration of intestinal homeostasis 3 days postabdominal irradiation. This study suggests that using the potential of hMSCs to home to various organs in response to tissue injuries could be a promising strategy to repair the radiation induced damages.