Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.