Wnt/β-catenin signaling is a major pathway in the liver, that we showed to be involved in the embryonic development of the liver (Decaens, Hepatology 2008), to be a key player of liver adult homeostasis by controlling liver metabolic zonation (Benhamouche, Dev Cell 2006), and to be a driver pathway initiating liver carcinogenesis (Colnot, PNAS 2004). To study β-catenin-dependent HCC (HCC-βcat), we have created genetically-modified mice such as the Apcko model in which liver cancers emerge due to β-catenin aberrant activation (Colnot, PNAS 2004), and we are currently using the CRISPR/Cas9 strategy to generate new models of HCC. These models are used both to identify how HCC-βcat emerge and progress, and to constitute preclinical models in which therapeutic opportunities arising from our basic research can be easily tested. This is of particular importance knowing the current landscape of HCC, in which HCC-βcat constitute a subclass which are predicted to be resistant to immunotherapies. Diagnosing these HCC and identifying precision medicine targeting specifically HCC-βcat are more than ever critical.