The scaffold protein Axin plays important roles in multiple signaling pathways through mediating the formation of different signaling complexes. Axin is best known for its role as a negative regulator in Wnt/β-catenin pathway. Aberrant activation of the key components in Wnt/β-catenin pathway including Axin has been linked to a variety of human cancers. Drugs developed for this pathway are far from satisfying largely due to the limited targets especially enzymesin this pathway. Almost all Axinsignal pathways depend on a number of protein-protein interactions (PPIs) for transmitting information, making PPIs attractive targets and probably a future direction for drug discovery. Axin interacts with a plethora of proteins, positively or negatively regulating several signaling pathways that are closely involved in the pathogenesis of human disease. Studies in recent years indicated Axin as a promising target for treating Wnt-driven diseases. With the identification of more interacting partners for Axin and increased understanding about the roles of these Axin-mediated PPIs in human disease, new targets may surface from the Axin PPI networks, which may lead to the generation of new drugs and treatmentstrategies. In this review, we outline the Axin PPI networks in several pathways especially in Wnt signaling and discuss how those Axin-interacting proteins affect the respective signaling pathways through an interaction with Axin.