The epidemiology of hepatocellular cancer (HCC) can be viewed from several important perspectives. The conventional perspective includes the overall public health impact of HCC, which is increasing in incidence in many regions of the world. The epidemiology of HCC can also be viewed from the perspective of variation in underlying disease associations such as viral hepatitis or the recently recognized link to nonalcoholic fatty liver disease (NAFLD). Of perhaps increasing importance with recent advances in therapy of HCC, the epidemiology of HCC can also be viewed from the perspective of variation in HCC biology. This lesser known perspective may depend in part on the underlying liver disease and the cell origin of the cancer, whether of hepatocyte or stem cell origin. This aspect is likely to become central to diagnosis and management of HCC with the further development of targeted therapeutics. The relative efficacy of these agents will likely depend on the biochemical pathways active in a given hepatocellular malignancy. This, in turn, is likely to be related to the epidemiological associations of HCC.