Current statistics indicate that hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related death. Major predisposing conditions are hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. To date treatment approach includes liver transplantation, surgical resection and or ablation, however; recurrence, metastasis, and mortality still remains high. Therefore, alternative treatments such as gene therapy is increasingly being considered as a feasible proposal. In this mini review we will focus on novel data of the past 10 years on the subject of gene therapy and hepatocellular carcinoma.