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Glioblastoma is the most common human brain cancer entity and is maintained by a glioblastoma stem cell (GSC) subpopulation. In this issue of the JCI, El-Sehemy and colleagues explored the effects that Norrin, a well- characterized activator of Wnt/[beta]-catenin signaling, had on tumor growth. Norrin inhibited cell growth via [beta]-catenin signaling in GSCs that had low expression levels of the transcription factor ASCL1. However, Norrin had the opposite effect in GSCs with high ASCL1 expression levels. The modulation of Norrin expression, with respect to high or low ASCL1 levels in GSCs, significantly reduced tumor growth in vivo, and subsequently increased the survival rate of mice. Notably, Norrin mediates enhanced tumor growth of glioblastomas by activating the Notch pathway. This study clarifies the opposing effects of Norrin on glioblastoma tumor growth and provides potential therapeutic targets for glioblastoma treatment., Norrin: a multifunctional signaling molecule Norrin is a secreted signaling molecule that activates canonical Wnt/[beta]-catenin signaling via binding to frizzled 4 (FZD4) or leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) [...]