Hepatocellular carcinoma (HCC) is a complex liver disease with limited treatment options and often resulting in a poor prognosis. The development of HCC depends on the formation of new blood vessels and it demonstrates hypervascularity and invasive property to the surrounding vasculature clinically. A complex network of growth factors acting on both tumor cells and endothelial cells mediates the angiogenesis in HCC. It is an attractive approach to inhibit the angiogenic processes as the treatment of HCC and therefore, anti-angiogenic TKIs were developed to inhibit the vessel formation in the tumors. However, it is currently perceived that the efficacy of these anti-angiogenic TKIs has reached plateau, and it is necessary to develop novel agents with non-TKI mechanism to inhibit the angiogenic targets. With the better understanding of molecular mechanisms that govern angiogenesis, as well as the advancement in biomedical engineering, new approaches of gene therapy have brought hopes for therapeutic intervention in HCC. Gene therapy is based on the transfer of genetic material to the patients with the aim to modify or correct the malignancy from its molecular basis. In this article, we will discuss the conventional anti-angiogenic therapies and the gene therapy approaches in HCC. The therapeutic potential of gene therapy for HCC treatment has been demonstrated and further development of anti-angiogenic may result in new treatment option for HCC patients.