Inhibitor of kappa B (I kappa B) kinase (IKK) phosphorylates I kappa B proteins, leading to their degradation and the liberation of nuclear factor kappa B for gene transcription. Here we report the crystal structure of IKK beta in complex with an inhibitor, at a resolution of 3.6 angstrom. The structure reveals a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD) and an elongated, alpha-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix-loop-helix motifs do not form these structures but are part of the SDD. The ULD and SDD mediate a critical interaction with I kappa B alpha that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDD mediates IKK beta dimerization, but dimerization per se is not important for maintaining IKK beta activity and instead is required for IKK beta activation. Other IKK family members, IKK alpha, TBK1 and IKK-i, may have a similar trimodular architecture and function.