Wnt regulation of β-catenin degradation is essential for development and carcinogenesis. β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of β-catenin precedes and is required for subsequent GSK-3 phosphorylation of β-catenin. This "priming" kinase is casein kinase Iα (CKIα). Depletion of CKIα inhibits β-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/β-catenin signaling. Our study uncovers distinct roles and steps of β-catenin phosphorylation, identifies CKIα as a component in Wnt/β-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.