The objectives of the present review is to update readers with the rapidly changing concepts in liver stem cell biology and related clinical applications. The liver has adapted to the inflow of ingested toxins by the evolutionary development of unique regenerative properties and responds to injury or tissue loss by rapid division of the mature cells, hepatocytes, and bile duct epithelial cells. Proliferation of the parenchymal cells is regulated by numerous cytokine/growth factor-mediated pathways and is timely synchronized with extracellular matrix degradation and the restoration of the vasculature. The putative role of stem cells in physiology, pathophysiology, and therapy is not yet precisely known but currently is under intensive investigation. Resident hepatic stem/ progenitor cells have been identified in small numbers and implicated in liver tissue repair, when hepatocyte and bile duct replication capacity is exhausted or experimentally inhibited. Several independent reports have suggested that bone marrow cells can give rise to different hepatic epithelial cells types, including hepatic stem cells, hepatocytes, and bile duct epithelium. These observations have resulted in the hypothesis that extrahepatic stem cells, specifically bone marrow-derived stem cells, are an important source for liver epithelial cell replacement, particularly during chronic injury. Most of published data, however, now suggest that they do not play a relevant role in replacement of epithelial cells in any known form of hepatic injury. In vitro differentiation protocols for various adult extrahepatic stem cells might eventually provide valuable sources of cells for transplantation and therapy. Amniotic epithelial stem cells, fetal liver progenitor cells as well as embryonic stem cells currently emerge as alternative stem cell sources and open new possibilities for cellular therapies of liver disease.