Abstract: Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors in the world. As an orallyavailable kinase inhibitor, sorafenib is the exclusively standard clinical treatment against advanced hepatocellular carcinoma. However, the increasing level of resistance to sorafenib has seriously affected the therapeutic effect. Herein, we review the potential mechanism of sorafenib resistance in hepatocellular carcinoma from the aspects of microenvironment, hypoxia, epithelial mesenchymal, cancer stem cells and so on.