HepaRG® cell model is a unique hepatic cell line in its ability to generate fully differentiated human hepatocytes and to express major hepatic functions for up to 4 weeks, including the main phase I and II metabolizing enzymes and hepatobiliary transporters. HepaRG® cell model has been widely used in virology, and for assessing (including for regulatory submissions) cytochrome P450 induction, deciphering xenobiotic modes of action, and studying biotransformation and genotoxic aspects. The reliability and robustness of HepaRG® cell model to predict hepatotoxicities, to mimic steatosis and steatohepatitis, and to document drug-drug interactions is reflected over the past decade by more than 800 publications. Moreover, HepaRG® cells can be genetically engineered in both proliferative and differentiated phases, for delivering ad hoc tools and unveiling gene function, regulation, and involvement in specific cellular pathways. In addition, recent development of 3D systems of HepaRG® cells either monocultured or cocultured with non-parenchymal liver cells open new avenues for mimicking still better the in vivo liver physiology and responses to xenobiotics.