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Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity, relapse and mortality rates. Multipotent mesenchymal stromal cells (MSCs) can be recruited to and become integral components of the HCC microenvironment and can influence tumor progression. This review discusses MSC migration to liver fibrosis and the HCC microenvironment, MSC involvement in HCC initiation and progression and the widespread application of MSCs in HCC-targeted therapy, thus clarifying the critical roles of MSCs in HCC.