The accuracy and the reliability of well-recognized clinical, virologic, histologic, and molecular risk factors for hepatocellular carcinoma (HCC) are still insufficient. Thus, accurate risk prediction of cancer development in individual patients with the aim of selecting high risk cohorts of patients for HCC chemoprevention programs remains an elusive goal. Future directions in chemoprevention of HCC will be in the development of molecular risk models and of new chemopreventive agents. Studies examining multiple genes and proteins (genomics and proteomics) in the same HCCs will be required to evaluate this possibility thoroughly. A strategy aiming at preventing chronic liver disease of any etiology (HCV and HBV infection, alcohol, obesity, others) may be required to prevent HCC in low and intermediate incidence areas, and hence, worldwide. In the setting of secondary chemoprevention, literature data pooling suggests a slight preventive effect of interferon (IFN) on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low, and the observed benefit might be due to spurious associations. The preventive effect is limited to sustained virological responders to IFN. So, there is no sound evidence to support a recommendation for widespread use of IFN to prevent HCC in HCV-related cirrhosis. In the setting of tertiary chemoprevention, the risk of recurrence of HCC may be reduced by IFN treatment in selected patient populations. Further large-scale multicenter randomized controlled trials may prove useful to evaluate the benefit on overall survival.