On a global scale, liver cancer is one of the leading causes of cancer morbidity and mortality. However, liver cancer rates vary substantially by country, with more than 80% of liver cancer cases occurring in the developing world. The major risk factors for hepatocellular carcinoma (HCC), the predominant histologic sub-type, are considered to be chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV) infection, exposure to aflatoxins, and excessive alcohol consumption; tobacco smoking and oral contraceptive use also may be associated with increased risk of HCC. This paper focuses on those risk factors that represent new targets for intervention, namely HBV and HCV infections and aflatoxin exposure. Childhood vaccination against HBV represents the greatest potential for reducing the liver cancer burden and could lead to the elimination of as much as 60% of all cases.