Copyright 2000 Academic PressNF-κB is a heterodimeric transcription factor that plays a key role in inflammatory and immune responses. In non-stimulated cells, NF-κB dimers are maintained in the cytoplasm through interaction with inhibitory proteins, the IκBs. In response to cell stimulation, mainly by proinflammatory cytokines, a multisubunit protein kinase, the IκB kinase (IKK), is rapidly activated and phosphorylates two critical serines in the N-terminal regulatory domain of the IκBs. Phosphorylated IκBs are recognized by a specific E3 ubiquitin ligase complex and undergo polyubiquitination which targets them for rapid degradation by the 26S proteasome. NF-κB dimers, which are spared from degradation, trans- locate to the nucleus to activate gene transcription. There is strong biochemical and genetic evidence that the IKK complex, which consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ, is the master regulator of NF-κB-mediated innate immune and inflammatory responses. In the absence of IKKγ, which normally connects IKK to upstream activators, no IKK or NF-κB activation can occur. Surprisingly, however, of the two catalytic subunits, only IKKβ is essential for NF-κB activation in response to proinflammatory stimuli. The second catalytic subunit, IKKα, plays a critical role in developmental processes, in particular formation and differentiation of the epidermis.