To identify functions of the IKKα subunit of IκB kinase that require catalytic activity, we generated an Ikkα^AA knockin allele containing alanines instead of serines in the activation loop. Ikkα^AA/AA mice are healthy and fertile, but females display a severe lactation defect due to impaired proliferation of mammary epithelial cells. IKKα activity is required for NF-κB activation in mammary epithelial cells during pregnancy and in response to RANK ligand but not TNFα. IKKα and NF-κB activation are also required for optimal cyclin D1 induction. Defective RANK signaling or cyclin D1 expression results in the same phenotypic effect as the Ikkα^AA mutation, which is completely suppressed by a mammary specific cyclin D1 transgene. Thus, IKKα is a critical intermediate in a pathway that controls mammary epithelial proliferation in response to RANK signaling via cyclin D1.