Even with modern 3D conformal treatments skin radiation injury can be an inadvertent complication associated with clinical radiotherapy particularly at tissue folds. It is also of concern in the context of a radiological terrorism incident or accident, since skin irradiation lowers the lethal dose of whole body radiation. We hypothesize that radiation-induced skin injury originates from a loss of stem and progenitor cells, accompanied by excessive ROS production and proinflammatory cytokines. Plerixafor, a CXCR-4 antagonist, is one of the most efficient bone marrow stem cell mobilizers and these studies were designed to experimentally assess the potential of Plerixafor to reduce skin radiation injury. The right hind legs of groups of C57BL/6 mice were exposed to radiation alone or in combination with Plerixafor. Plerixafor was administered intraperitoneally at a dose of 5 mg/kg given in two doses separated by two days and started either on day 0, 4, 7, 15 or 24 after irradiation. The primary end point was skin injury, which was assessed three times a week for at least 2 months using a semi-quantitative scale. Secondary end points measured at selected time points included histology (primarily H&E) and cytokine levels (TGF-β and TNF-α). The acute and late skin injury in mice receiving Plerixafor was highly dependent on the timing of administration of the drug. The maximum benefit was observed when the drug was started 1 week after radiation exposure, and earlier or later administration of the drug decreased its efficacy. Secondary damage end points (cytokine levels and histologically assessed tissue thickness) provided confirmatory observations. In an attempt to gain insight into the effect of timing of administration of the agent on the mitigation effect, the ligand to CXCR4, stromal derived factor, SDF-1, was measured as a function of time after radiation exposure. Expression of SDF-1 monitored in skin as a function of time after a 30 Gy radiation exposure suggested a strong correlation between timing of administration of Plerixafor and expression of SDF-1 in irradiated skin: optimum drug administration timing coincided with maximal SDF-1 expression in the skin of irradiated mice. This report presents the first observation that CXCR4 antagonist improves both acute and late skin response to radiation exposure.