The transforming growth factor type β-1 (TGF-β) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IκB kinase α (IKKα) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKKα in TGF-β signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKα and components of the TGF-β signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKα and the TGF-β signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKα to the nucleus, defective TGF-β-induced growth arrest was rescued by introduction of a constitutively nuclear IKKα variant. These results suggest that the tumor-suppressive activity of IKKα in stratified epithelia may be exerted in part via the TGF-β signaling pathway.