Simple SummaryWnt signaling is one of the main evolutionarily conserved developmental pathways needed to instruct embryo formation and maintenance of organ tissues. Decades of research also clearly recognize the fundamental role of Wnt signaling during carcinogenesis. Indeed, dysregulation of Wnt pathway components has been suggested as a relevant hallmark of several neoplastic malignancies. In this review, we summarize the main molecular mechanism through which the Wnt pathway exerts its intracellular effects, with a specific focus on brain development and brain tumors, and how Wnt interacts with the surrounding brain environment. In this context, we review the latest anti-cancer therapeutic approaches employed to specifically target Wnt signaling in cancer, and their potential application in the brain tumor context. Moreover, we discuss the additional efforts that will be needed to define the real clinical impact of Wnt modulation in different types of brain tumors and even how to overcome the unsolved concerns about the potential systemic effects of such therapeutic approaches.AbstractThe involvement of Wnt signaling in normal tissue homeostasis and disease has been widely demonstrated over the last 20 years. In particular, dysregulation of Wnt pathway components has been suggested as a relevant hallmark of several neoplastic malignancies, playing a role in cancer onset, progression, and response to treatments. In this review, we summarize the current knowledge on the instructions provided by Wnt signaling during organogenesis and, particularly, brain development. Moreover, we recapitulate the most relevant mechanisms through which aberrant Wnt pathway activation may impact on brain tumorigenesis and brain tumor aggressiveness, with a particular focus on the mutual interdependency existing between Wnt signaling components and the brain tumor microenvironment. Finally, the latest anti-cancer therapeutic approaches employing the specific targeting of Wnt signaling are extensively reviewed and discussed. In conclusion, here we provide evidence that Wnt signaling, due to its pleiotropic involvement in several brain tumor features, may represent a relevant target in this context, although additional efforts will be needed to: (i) demonstrate the real clinical impact of Wnt inhibition in these tumors; (ii) overcome some still unsolved concerns about the potential systemic effects of such approaches; (iii) achieve efficient brain penetration.