Distinct mechanisms are believed to regulate growth of the liver during fetal development and after injury in adults, because the former relies on progenitors and the latter generally involves replication of mature hepatocytes. However, chronic liver injury in adults increases production of Hedgehog (Hh) ligands, developmental morphogens that control progenitor cell fate and orchestrate various aspects of tissue construction during embryogenesis. This raises the possibility that similar Hh‐dependent mechanisms also might regulate adult liver regeneration. The current analysis of murine liver regeneration after 70% partial hepatectomy (PH), an established model of adult liver regeneration, demonstrated that PH induced production of Hh ligands and activated Hh signaling in liver cells. Treatment with a specific Hh signaling inhibitor interfered with several key components of normal liver regeneration, significantly inhibiting progenitor responses, matrix remodeling, proliferation of hepatocytes and ductular cells, and restoration of liver mass. These global inhibitory effects on liver regeneration dramatically reduced survival after PH. Conclusion: Mechanisms that mediate liver organogenesis, such as Hh pathway activation, are retained and promote reconstruction of adult livers after injury. Hepatology 2010