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The multiple origin of cancer stem cells in hepatocellular carcinoma. Hepatocellular carcinoma (HCC) accounts for approximately 6% of all new cancer cases diagnosed, and due to its aggressiveness, it is the second most common cause of cancer mortality worldwide. Based on different etiological factors, genetic backgrounds, and longtime development of the disease, HCC is characterized by a high phenotypic and functional heterogeneity. Tumor variability occurs both among patients (intertumoral heterogeneity) and within a single tumor (intratumoral heterogeneity). The intratumoral heterogeneity, in particular the variability of the markers of cancer stem cells (CSC) population may determine specific behavior and prognosis of the tumor. Understanding the cellular mechanisms originating CSC will provide an important hint in the management of HCC. The characterization of the cells of origin of cancer can have significant implication in early diagnosis, in the development of appropriate therapies and in the prevention of relapse. Here, we review recent evidences on the possible cellular origin of CSC that play a role in the heterogeneity of the HCC.