Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major risk factors for HCC development are now well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. However, no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Malignant transformation of hepatocytes may occur as a consequence of various etiologies, such as chronic viral hepatitis, alcohol, and metabolic disorders, in the context of increased cellular turnover induced by chronic liver injury, regeneration and cirrhosis. Activation of cellular oncogenes, inactivation of tumor suppressor genes, overexpression of certain growth factors, and possibly telomerase activation and DNA mismatch repair defects may contribute to the development of HCC. Finally, aflatoxins have been shown to induce specific mutations of the p53 tumor suppressor gene, thus pointing to the contribution of environmental factors to tumor development at the molecular level.