A better understanding of the liver's response to toxic injury, which includes hepatocyte proliferation, activation and differentiation of facultative hepaic stem cells (oval cells), and - unfortunately - an increased risk for hepatocellular carcinoma, is a prerequisite for the development of novel clinical treatments for chronic liver disease and improved cancer prevention. Likewise, cell replacement therapy, either through direct hepatocyte transplantation or in bio-artificial liver devices, needs to be improved in order to become a reliable alternative to liver transplantation. To date, investigations of hepatocyte proliferation have frequently focused on the partial hepatectomy paradigm, a noninjury model that is not reflective of liver injury in humans and which has therefore failed to identify specifi targets for either improved regeneration following toxic injury or for limiting proliferation in HC in humans. In Specific Aim 1, we will determine which genes and gene combinations promote or repress hepatocyte repopulation following toxic liver injury using an innovative genetic approach. In Specific Aim 2, we will employ expression of key hepatic transcription factors to improve the differentiation of hepatic progenitor cells to functional hepatocytes. Together, these approaches will provide an improved understanding of the liver's response to toxic injury, and facilitate the discovery of new cell replacement therapies to treat chronic liver disease and liver failure.