Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in our country. In recent years, with deepening research in HCC pathology and molecular biology mechanism, small molecular drug research targeting HCC has made substantive progress and become one of effective systemic therapies for HCC. This review summarized the reaction mechanism, constitutional characteristic and recent progress of small molecule inhibitors in the clinic and clinical stage targeting HCC, including angiogenesis inhibitors, inhibitors of epidermal growth factor receptor, inhibitors of the key signal transduction passways and epigenetic target inhibitors. Finally, we proposed that multi-target inhibitors will be the main research direction in the drug development of anti-HCC, and dual targeting epigentic targets and kinases may result in promising therapeutic effects againist HCC.