Whether the stem cells or the mature cells are the origination of hepatocellular carcinoma is uncertain. Recently, researches have shown that some cancer stem cells could derive from adult stem cells. Moreover, gastric cancer could originate from bone marrow stem cells. Hematopoiesis and the hepatic environment are known to have a close relationship at the time of hepatic development and systemic diseases. Here we propose a new carcinogenetic model of hepatocellular carcinoma. Chronic liver injury could recruit bone marrow stem cells to the liver. Bone marrow cells take part in liver regeneration by differentiating to oval cells and hepatocytes. Persistent regeneration results in hyperproliferation, an increased rate of transforming mutations. Extracellular matrix remodeling triggers a cascade of events that inhibits the transactivation potential of liver-specific transcription factors, blocks the maturation of stem cells, and then results in hepatocellular carcinoma.