Liver cancer is the third most common cause of cancer mortality in the world. Most of the liver cancers arise in the cirrhotic liver suggesting that the deregulation of liver progenitor or stem cell pool underlying the liver cirrhosis might play an important role in the formation of hepatocellular carcinoma (HCC). In malignant tumors a relatively small population of cells, termed cancer stem cells, is capable of initiating and maintaining the disease. The possible origins and the pathways sustaining these cells are not known yet. Akt and Wnt signalling pathways, which are important in maintenance of the stem cell compartments of different tissues including liver are frequently deregulated in HCC. Here we utilize protein complementation assay (PCA)-based screening methodology to find inhibitors of the Wnt and AKT pathways playing major role in maintenance of the HCC. These compounds will be tested in vitro using sorted normal liver and liver cancer stem cells and utilizing mouse models of HCC in vivo. The possible additive effect of complex treatment using identified AKT and Wnt inhibitors and previously identified re-activator of p53 pathway will be evaluated. Our goal is to provide at least one validated inhibitor of both Wnt and AKT pathways, which could be used as lead compounds in designing clinically usable therapeutics.