The nuclear factor-kappa B (NF-κB) family of transcription factors plays a seminal role in inflammation, apoptosis, development, and cancer. Modulation of NF-κB-mediated gene expression in response to diverse signals is coordinated by the IκB kinase (IKK) complex. We identified ELKS, an essential regulatory subunit of the IKK complex. Silencing ELKS expression by RNA interference blocked induced expression of NF-κB target genes, including the NF-κB inhibitor IκBα and proinflammatory genes such as cyclo-oxygenase 2 and interleukin 8. These cells were also not protected from apoptosis in response to cytokines. ELKS likely functions by recruiting IκBα to the IKK complex and thus serves a regulatory function for IKK activation.