We hypothesized that stem cell factor (SCF) is a critical mediator of restenosis facilitating mobilization, homing and transdifferentiation of progenitors. Femoral injury was induced in wildtype, WBB6F1 (W/W^v) (c-kit deficient) and WCB6F1 (Sl/Sl^d, Steel-Dickie) (mSCF deficient) mice and neointimal formation, SCF, c-kit, SMA and MMP-9 quantified. Progenitor cell mobilization was evaluated by circulating SCF levels and CD34+ cells. Vascular injury following BM transplantation using donor cells expressing eYFP (BMT^Yfp®Wild) was performed. The effects of SCF and SMCs on Lin^– BM cell adhesion to fibronectin was studied in addition to coculture of eYFP⁺ Lin^– BM cells with activated SMC. The effects of PDGF and A-II on SCF expression following vascular injury were evaluated, as were the effects of long-term ACEI. W/W^v and Steel-Dickie mice exhibited marked attenuation in neointimal formation at day 14 and 28 (P<0.001) In wild-type mice vascular injury resulted in the elevation of sSCF compared to Steel-Dickie mice and induced an increase in circulating CD34⁺ progenitors (P<0.01). An increase in SCF, proMMP-9 and MMP-9 expression in the adventitia occurred within the first week following vascular injury. BMT^Yfp®Wild indicated the presence of c-kit positive cells within the medial layer expressing SMA. SCF induced a marked increase in adhesion of BM cells to fibronectin suggesting a direct role of SCF in progenitor recruitment (P<0.001). Activated rat SMCs increased the adhesion of BM cells and coculture of eYFP Lin^– BM cells with SMC showed clusters of cells expressing both eYFP and SMA, suggesting that SMC activation, marked by SCF expression, is required for progenitor differentiation. PDGF and A-II upregulated SMCc SCF expression in a dose dependent fashion, and ACEI (BMT^Yfp®Wild) suppressed the number of BM derived neointimal cells(P<0.01). In conclusion, vascular injury upregulates local mSCF expression and activates MMP-9, facilitating the shedding of sSCF with resultant mobilization and homing of BM progenitors to sites of vascular injury. In-vivo deficiency of SCF or its receptor, c-kit is associated with reduced neointimal formation. Targeting SCF may serve as a novel therapeutic strategy for restenosis.