Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.