Hepatocellular carcinoma (HCC) is a one of the most prevalent cancers worldwide, especially in the Asia Pacific region. At present, the five-year survival of individuals with HCC is low, mainly due to the late presentation of the disease, and limited therapeutic options. The major risk factors for HCC in the Asia Pacific region include hepatitis B and C viral infection. Removing or reducing these risk factors, such as by immunizing against the hepatitis B virus, may reduce the incidence of hepatitis B-associated HCC in the distant future. However, immunization does not decrease the risk of HCC in individuals who are currently infected with HBV worldwide highlighting the continued importance of examining strategies for the treatment of HCC. Current treatment strategies include surgical resection, liver transplantation, chemotherapy, transcatheter arterial chemoembolism and percutaneous injection. Except for surgical resection and liver transplantation, which represent the most viable treatment options, most of the other present treatments are mainly for palliation. Hence novel treatment modalities continue to be investigated and several of these are currently in clinical trials. One of the more promising novel approaches for HCC treatment is gene therapy. Potential promising gene therapeutic approaches for the treatment of HCC include augmentation of tumor suppressor genes, inhibition of abnormally over-expressed oncogenes as well as specifically inducing death of cancer cells either via “suicide” gene therapy, conditional replicative adenovirus strategy, immunomodulation or inhibiting tumor angiogenesis. Nonetheless, successful implementation of these gene therapeutic approaches is dependent on overcoming current practical and technical hurdles underscoring the need for a better understanding of the basic aspects of gene therapy.