Wnt/beta-catenin signaling is critically important during development and for stem cell maintenance. Dysregulation of the Wnt pathway is implicated in numerous diseases, most notably cancer. Appropriate manipulations for intervention and therapy require an accurate understanding of the Wnt signaling mechanism. The consensus model for the Wnt pathway is surprisingly straightforward: In the OFF state of the pathway, the central regulator in the pathway, termed the destruction complex (DC) targets beta-catenin for degradation, thereby preventing it from nuclear signaling. In the ON state, ligand activation of the Wnt receptor inhibits DC activity, leading to beta-catenin accumulation and transcription of Wnt target genes.