Fetal hepatoblasts are bipotential progenitor cells that differentiate into hepatocytes and cholangiocytes. We hypothesize that hepatoblasts are tumor-initiating cells, and that dysregulation of signaling pathways involved in cell differentiation leads to malignant transformation of hepatoblasts into cancer cells (Figure 1). We employ mouse models of carcinogenesis as well as xenograft models of human liver cancer to test our hypothesis.