The chapter discusses the role of the Wnt signaling pathway in cancer, focusing on the molecular defects that promote neoplastic transformation in humans and animal models. The Wnt pathway involves several key components, including β-catenin, GSK3β, dishevelled (Dvl), axin, and APC. β-Catenin, a key regulator of cell growth and survival, is stabilized by mutations in the *CTNNB1* gene, leading to the activation of gene transcription. These mutations are often found in colorectal cancers and other types of cancers, such as hepatocellular carcinoma (HCC) and endometrial cancers. The chapter also highlights the importance of other components like GSK3β, which can be inactivated by Frat-1, and axin, which is a tumor suppressor that binds to β-catenin and APC. Additionally, the chapter explores the cross-talk between the Wnt pathway and other signaling pathways, such as TGF-β and retinoid signaling, and the potential for new mechanisms of gene activation by β-catenin. Overall, the Wnt pathway's dysregulation through various genetic defects contributes to cancer development and progression.The chapter discusses the role of the Wnt signaling pathway in cancer, focusing on the molecular defects that promote neoplastic transformation in humans and animal models. The Wnt pathway involves several key components, including β-catenin, GSK3β, dishevelled (Dvl), axin, and APC. β-Catenin, a key regulator of cell growth and survival, is stabilized by mutations in the *CTNNB1* gene, leading to the activation of gene transcription. These mutations are often found in colorectal cancers and other types of cancers, such as hepatocellular carcinoma (HCC) and endometrial cancers. The chapter also highlights the importance of other components like GSK3β, which can be inactivated by Frat-1, and axin, which is a tumor suppressor that binds to β-catenin and APC. Additionally, the chapter explores the cross-talk between the Wnt pathway and other signaling pathways, such as TGF-β and retinoid signaling, and the potential for new mechanisms of gene activation by β-catenin. Overall, the Wnt pathway's dysregulation through various genetic defects contributes to cancer development and progression.