Epidemiologic, clinical, and virologic data have shown a close association between chronic infection with hepatitis C virus (HCV) and the development of hepatocellular carcinoma (HCC). In many countries of the developed world, HCV infection accounts for more than half of the cases of HCC. HCC usually arises after 2-4 decades of infection, typically in the context of an underlying cirrhosis. Treatment of hepatitis C with interferon-alfa can lead to sustained clearance of HCV, and small prospective studies as well as larger retrospective analyses suggest that interferon therapy leads to a decrease in the incidence of HCC. Without a reliable tissue culture system or a small animal model of HCV infection, analysis of the mechanisms by which HCV leads to cancer has been difficult. Nevertheless, both in vitro expression systems and in vivo transgenic mice studies suggest that HCV has an inherent carcinogenic potential. Understanding the pathogenesis of HCV-associated HCC is important in developing effective means of prevention and treatment of this highly malignant form of cancer.