The NF-?B/Rel transcription factors are present in the cytosol in an inactive state, complexed with the inhibitory I?B proteins. Most agents that activate NF-?B do so through a common pathway based on phosphorylation-induced, proteasome-mediated degradation of I?B. The key regulatory step in this pathway involves activation of a high molecular weight I?B kinase (IKK) complex whose catalysis is generally carried out by three tightly associated IKK subunits. IKK? and IKK? serve as the catalytic subunits of the kinase and IKK? serves as the regulatory subunit. Activation of IKK depends upon phosphorylation at Ser177 and Ser181 in the activation loop of IKK? (Ser176 and Ser180 in IKK?), which causes conformational changes, resulting in kinase activation.