Osteopontin (OPN) produced by cells of the immune system, epithelial tissue, smooth muscle cells, osteoblasts and tumor cells has been implicated in various pathophysiological functions such as cell binding, spreading and migration, and tumor metastasis. OPN is known to bind to integrins expressed on macrophages through the arginine-glycine-aspartic acid (RGD) motif and promote migration of cells resulting in granuloma. In the liver, it has been reported that hepatic Kupffer cells secrete OPN facilitating macrophage infiltration in necrotic areas following carbon tetrachloride liver toxicity. Recent work has underlined the importance of OPN as a pivotal cytokine/chemokine in the generated hepatic neutrophil response during early phase alcoholic liver injury. Increased hepatobiliary OPN expression correlated well with higher neutrophil infiltration in a rat model of alcoholic steatohepatitis. In the same model of alcoholic steatohepatitis, higher hepatic expression of OPN in females was attributed to the higher neutrophil infiltration and consequent higher female sensitivity to liver damage. OPN as a potential biomarker for inflammatory liver disease has also been recently assessed. This review will focus on studies demonstrating the role of OPN in mediating hepatic inflammation (neutrophils, monocytes/macrophages and lymphocytes) and the ensuing liver toxicity.