Recent studies indicated the importance of stem cells in cancer, including in hepatocellular carcinoma. The presence of the stem cells and cancer stem cells in liver diseases is associated with the initiation, maintenance, metastasis and chemoresistance. Since hepatocellular carcinoma is a heterogeneous disease with a wide variety of prognostic types, which may limit the efficiency of standardized therapy, the understanding of the source of the cancer, alteration in important molecular signaling pathways and interaction between cancer cells and other cells types will be important in defining future, tailored treatment strategies.