Infection with HBV and HCV are considered the most important etiological factors for hepatocellular carcinoma (HCC). Current treatment options are insufficient, creating an urgent need for new therapeutic strategies that inhibit disease progression and improve survival in patients with HCC. A promising strategy for the treatment of HCC is gene therapy (GT), which is characterized by the transduction of tumor cells with genes displaying antitumor properties, such as pro-apoptotic, suicide, anti-angiogenic and immunomodulatory genes, as well as siRNAs. Other GT strategies have investigated oncolytic viral vectors that propagate specifically in tumor cells and, subsequently, kill these malignant cells. Furthermore, GT strategies directed toward halting virus proliferation, such as genetic vaccines or genetic interference with viral replication, as well as strategies that prevent viral induced pre-carcinogenic changes, represent the most efficient strategies to prevent HCC development. These GT approaches are promising alternatives to, and could complement or substitute, current treatment options for HCC. This review summarizes trends in GT during the past decade, including investigations in animal models and patients for the prevention and treatment of hepatitis virus-induced HCC.