A major advance in the understanding of NF-κB regulation came with the identification of the multisubunit IKK kinase complex, which contains two catalytic subunits, IKK-α and IKK-β, and the regulatory subunit IKK-γ (NF-κB essential modulator [NEMO])(reviewed in ref. 6). The predominant form of the IKK complex is an IKK-α/IKK-β heterodimer associated with IKK-γ, and this association is mediated by the interaction of IKK-β and IKK-γ. IKK-γ is not a kinase per se but is absolutely essential for NF-κB activation by multiple activators. Since the identification of the IKK complex, attention has focused on the upstream kinases of different signal transduction pathways and how these pathways converge on the IKK complex. These kinases include NF-κB–inducing kinase (NIK), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEKK1), TGF-β–activated kinase (TAK1), Cot/Tpl-2, protein kinase R (PKR), PKC, Akt (or PKB), and mixedlineage kinase 3 (MLK3). Once activated, IKK-β becomes autophosphorylated at a carboxy terminal serine cluster, which decreases IKK activity and prevents prolonged NF-κB activation by negative autoregulation. Mice deficient in IKK-β and IKK-α have recently been created; ikk–/–mice die at about 14 days of gestation due to massive hepatic cell apoptosis, a phenotype remarkably similar to that seen in mice deficient in the RelA (p65) subunit of NF-κB. This phenotype may be due to the loss of the antiapoptotic effects of NF-κB, since NF-κB activation is decreased after TNF-α or IL-1 treatment of knockout fibroblasts. In contrast, mice lacking IKK-α maintain functional NF-κB activation but exhibit profound epidermal and morphogenic abnormalities and die in utero or soon after birth (6). These perplexing phenotypes hint that the IKK subunits are associated with still-undefined functions.