Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell–derived factor‐1α (SDF‐1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF‐1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF‐1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture‐induced activation. Treatment of stellate cells with recombinant SDF‐1α increases expression of α‐smooth muscle actin and collagen I and stimulates a dose‐dependent increase in HSC proliferation. Inhibitor studies suggest that SDF‐1α/CXCR4‐dependent extracellular signal‐regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. Conclusion: HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF‐1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal‐regulated kinase 1/2 and phosphoinositide 3‐kinase pathways mediate SDF‐1α–induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches. (HEPATOLOGY 2009.)