While MSCs are intriguing candidates for stem cell-based regenerative therapy to treat numerous liver ailments, further study is needed to improve their therapeutic advantages. By delivering particular genes or trophic factors to wounded liver tissues, genetic engineering boosts MSC's therapeutic efficacy. Moreover, overexpression of foreign genes in damaged liver tissues will improve the hepatogenic differentiation, homing, anti-inflammatory, immunosuppressive, anti-apoptotic, antifibrotic, and cancer capacities of MSCs. MSCs are transformed into HLCs with mature hepatocyte capabilities when transcription factors are supplied; however, HLCs derived from genetically modified MSCs are not used to treat liver disease.This is because, after extended growing in vitro, both primary hepatocytes and HLCs lose their liver-specific functions. Difficulty in using genetic engineering in MSCs. For starters, there is no recognized genetic modification approach to homogenize the functional features of MSCs, resulting in substantial variation in surface marker expression, proliferation, and differentiation in gene-modified MSCs. Second, MSC genetic alteration creates safety issues and unpredictability, such as tumor development or in vivo differentiation. In the future, new techniques with effective gene carriers, appropriate transfection conditions, good targeted specificity and lesser cytotoxicity should be developed. As MSCs respond variably to local microenvironments, people with distinct liver illnesses may have variable responses to genetically altered MSC transplantation. Finally, we underline that all scientific challenges must be resolved before genetically modified MSC therapy may be employed in clinical practice for liver problem patients.