The liver can regenerate itself through the progenitor cells it harbors. Here we demonstrate isolation of epithelial progenitor/stem cells from the fetal human liver, which contains a large number of hepatoblasts. Progenitor liver cells displayed clonogenic capacity, expressed genes observed in hepatocytes, bile duct cells and oval cells, and incorporated genes transferred by adenoviral or lentiviral vectors. Under culture conditions, progenitor cells proliferated for several months, with each cell undergoing more than forty divisions, but they retained normal karyotypes. Progenitor cells differentiated into mature hepatocytes in mice with severe combined immunodeficiency, both when in an ectopic location and when in the liver itself. Cells integrated in the liver parenchyma and proliferated following liver injury. An abundance of progenitor cells in the fetal human liver is consistent with models indicating depletion of progenitor/stem cells during aging and maturation of organs. The studies indicate that isolation of progenitor cells from fetal organs will be appropriate for establishing novel systems to investigate basic mechanisms and for cell and gene therapy.