Hepatocellular carcinoma (HCC) is the major malignancy of the liver; it is the third leading cause of cancer-related deaths globally. Despite advances in treatments for HCC, prognosis remains bleak, with most patients eventually dying within 2 years after diagnosis. More effective therapy for HCC is needed. The lack of effective treatment options for HCC is at least in part due to our lack of understanding the pathogenesis of this disease. Identifying novel pathway(s) that are responsible for HCC could be translated into targeted therapy and improve the outcomes of these patients. SALL4 is a stem cell factor that plays an important role during early development and is part of the key embryonic stem cell transcriptional regulatory network. SALL4 is also recognized as an oncogene and has been used as a specific diagnostic marker for various solid tumors, such as germ cell tumor and acute myeloid leukemia. Based on vigorous statistical analyses and experimental models, we have recently reported that SALL4 is an independent prognostic factor and potential therapeutic target for HCC. Importantly, we have also identified a therapeutic peptide that can effectively target the oncogenic functions of SALL4. In this RO3 application, we plan to evaluate the role of Sall4 in HCC development using both loss and gain-of function murine models. While the gain-of-function murine model will be useful to test future SALL4 inhibitors as a new class of HCC drugs, the loss-of- function murine model will help us understand whether Sall4 plays an essential role in the initiation and/or progression of HCC. The knowledge gained will help us to better understand the mechanism(s) for hepatocarcinogenesis and lay the foundation for future more efficient targeted therapy development.