Liver cancer is the second leading cause of cancer mortality worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, constituting more than 85% of hepatic malignancies. Currently, there are only limited therapeutic options. Innovative research on the pathogenesis of this disease at the molecular and cellular levels is needed to improve its diagnosis and develop novel treatment strategies. The liver is an organ with extraordinary regeneration capacity upon damage. It consists of two main epithelial cell lineages: hepatocytes and cholangiocytes. It has long been proposed that facultative stem cells exist in the liver lobular region next to bile ducts formed by cholangiocytes. These stem cells produce intermediate (progenitor) cells that give rise to cholangiocytes and mature hepatocytes. However, recent genetic lineage tracing studies suggest that the adult hepatocyte population is primarily replenished through self-renewal. Moreover, emerging evidence has unravelled the heterogeneity of hepatocytes in both metabolism function and regenerative capability according to their zonal location in the liver lobule. HCC is believed to mainly originate from the transformation of normal hepatocytes through a series of genetic alterations. However, the role of distinct zonal subsets of hepatocytes in the liver regeneration and initiation/progression of HCC is poorly understood. We have developed multiple mouse models to systematically trace the fate and function of discrete zonal hepatocyte subsets in liver maintenance and regeneration. These mouse models are also utilized to identify the cellular origin of tumours and the correlations in molecular signatures between a normal hepatocyte subset and the tumours arising from it. A better understanding of the role of distinct zonal hepatocytes in liver homeostasis and regeneration, and identification of the critical target cell populations and molecular mechanisms for HCC development from our studies would potentially lead to novel strategies for earlier detection and more effective therapies for HCC patients.