Hepatocyte-like cells (HLCs) generated from various human pluripotent stem cells (hPSCs), mostly induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) or direct cell conversion and also other stem cells like gestational tissues stem cells and mesenchymal stromal cells; provide potential cell sources for biomedical applications. Liver transplantation is the gold standard treatment for patients with end stage liver disease, but there are many practical limits, mostly insufficient number of donated healthy livers. Meanwhile the number of patients to receive a liver organ transplant for a better life is increasing. In this regard, HLCs may provide an adequate cell source to overcome these shortages. New molecular engineering approaches such as CRISPR/Cas systen with iPSCs technology provid the basic principles of gene correction for monogenic inherited metabolic liver diseases as another application of HLCs. It has shown that HLCs could replace primary human hepatocytes in drug discovery and hepatotoxicity tests. However, generation of fully functional HLCs is still a big challenge; research groups have been trying to improve current differentiation protocols to achieve better HLCs according to morphology and function of cells. Large-scale generation of functional HLCs in bioreactors could make a new window in producing enough hepatocytes for treating end-stage liver patients as well as other biomedical applications such as drug studies. In this review, regarding the biomedical value of hepatocyte-like cells, we focus on the current and efficient approaches for generating hepatocyte- like cells in vitro and discuss about their applications in regenerative medicine and drug discovery.