Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, with over a million new cases annually. It is generally advanced upon detection due to underlying liver disease, which further complicates treatment. Most of the therapeutic strategies in current use (surgery, transplantation, irradiation or chemotherapy) are either palliative or only of benefit to a small percentage of patients. This article reviews the biology of HCC, including many of the molecular changes and mechanisms leading to HCC development. This article discusses the recent innovative strategies to interfere with the progression of HCC, including novel gene therapy strategies. The most recent data supporting the use of immunotherapy for hepatocellular cancer is reviewed in detail.