Wnt ligands bind to transmembrane receptors of the Frizzled family. Secreted factors such as WIFs and SFRPs compete with Wnt ligands for binding. Activated receptor signals through Dishevelled and Casein kinase 1 (CK1) to a protein complex containing glycogen synthase kinase–3 (GSK3), axis inhibition protein 1 (Axin), and APC. The APC complex constitutively directs β-catenin ubiquitination and degradation. The Wnt signal inhibits the APC complex, leading to β-catenin stabilization and accumulation in the nucleus. Nuclear β-catenin binds T cell factor (Tcf) transcription factors to drive expression of genes such as c-Myc and Cyclin D1 that support cell growth, proliferation, and survival. Oncogenes are shown in green; tumor suppressor genes are shown in red. In this issue of the JCI, Kansara et al. provide evidence that WIF1 is a tumor suppressor and that epigenetic silencing of WIF1 accelerates osteosarcomagenesis (17).