Members of the nuclear factor kappa B (NF-κB) family of dimeric transcription factors (TFs) regulate expression of a large number of genes involved in immune responses, inflammation, cell survival, and cancer. NF-κB TFs are rapidly activated in response to various stimuli, including cytokines, infectious agents, and radiation-induced DNA double-strand breaks. In nonstimulated cells, some NF-κB TFs are bound to inhibitory IκB proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of IκB proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of IκB proteins liberates IκB-bound NF-κB TFs, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. Most of the IKKα and IKKβ molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKKγ or NEMO. Despite extensive sequence similarity, IKKα and IKKβ have largely distinct functions, due to their different substrate specificities and modes of regulation. IKKβ (and IKKγ) are essential for rapid NF-κB activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor α (TNFα) or lipopolysaccharide (LPS). In contrast, IKKα functions in the activation of a specific form of NF-κB in response to a subset of TNF family members and may also serve to attenuate IKKβ-driven NF-κB activation. Moreover, IKKα is involved in keratinocyte differentiation, but this function is independent of its kinase activity. Several years ago, two protein kinases, one called IKKε or IKK-i and one variously named TBK1 (TANK-binding kinase), NAK (NF-κB–activated kinase), or T2K (TRAF2-associated kinase), were identified that exhibit structural similarity to IKKα and IKKβ. These protein kinases are important for the activation of interferon response factor 3 (IRF3) and IRF7, TFs that play key roles in the induction of type I interferon (IFN-I). Together, the IKKs and IKK-related kinases are instrumental for activation of the host defense system. This Review focuses on the functions of IKK and IKK-related kinases and the molecular mechanisms that regulate their activities.