Hepatocellular carcinoma (HCC) is part of the natural history of non-alcoholic steatohepatitis (NASH). A significant proportion of people who have cryptogenic cirrhosis develop HCC. NASH-related cirrhosis carries a substantial risk for early HCC development. Diagnosis of HCC often is made at first referral; the tumor usually is large with multiple localizations. Patients who have obesity or diabetes are at risk for HCC and a variety of cancers. Given the epidemic of obesity and diabetes, the incidence of NASH-related HCC is expected to increase. In addition to developing new diagnostic tools and pharmacologic therapies, efforts should be directed at preventing non-alcoholic fatty liver disease.