Cytokine-induced activation of the IκB kinases (IKK) IKK-α and IKK-β is a key step involved in the activation of the NF-κB pathway^,,,. Gene-disruption studies of the murine IKK genes have shown that IKK-β, but not IKK-α, is critical for cytokine-induced IκB degradation^,,. Nevertheless, mouse embryo fibroblasts deficient in IKK-α are defective in the induction of NF-κB-dependent transcription^,,. These observations raised the question of whether IKK-α might regulate a previously undescribed step to activate the NF-κB pathway that is independent of its previously described cytoplasmic role in the phosphorylation of IκBα. Here we show that IKK-α functions in the nucleus to activate the expression of NF-κB-responsive genes after stimulation with cytokines. IKK-α interacts with CREB-binding protein and in conjunction with Rel A is recruited to NF-κB-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone H3. These results define a new nuclear role of IKK-α in modifying histone function that is critical for the activation of NF-κB-directed gene expression.