Hepatocellular carcinoma (HCC) is the most frequent tumor of the liver, and in contrast to the reduction in the number of deaths in many common cancers, HCC’s mortality rates have gone up in recent years. One of the features that characterizes HCC is the activation of the Wnt/β-catenin signaling. Recent preclinical testing in HCC models has shown a reduction in tumor growth using siRNA or ASOs acting as β-catenin inhibitors.