In the liver, several cell types have the longevity that is needed to be the cell of origin of a cancer: hepatocytes, cholangiocytes and progenitor cells. The latter are located in the most peripheral branches of the biliary tree, the ductules and canals of Hering. The most important risk factors for liver cancer are chronic viral hepatitis B and C and alcoholic and non-alcoholic steatohepatitis. In these and other chronic liver diseases, progenitor cell activation is seen, rendering them a target cell population for carcinogenesis. The degree of activation is positively correlated with the inflammatory activity and the stage of the disease. Recently, it has been shown that in the cirrhotic stage of most chronic liver diseases, the hepatocytes become senescent owing to telomere shortening. This makes it even more plausible that at least part of the hepatocellular carcinomas originate from a progenitor cell. Hepatocellular carcinomas expressing progenitor cell/ductular markers like cytokeratin 19 have a more aggressive clinical course. It is therefore important to recognize this entity.