Inflammation and innate immunity involve signalling pathways leading to the production of inflammatory mediators. Usually such responses are self-limiting, but aberrant resolution of inflammation results in chronic diseases. Much attention has focused on pro-inflammatory signalling but little is known about the mechanisms that resolve inflammation. The IκB kinase (IKK) complex contains two catalytic subunits, IKKα and IKKβ, and controls the activation of NF-κB transcription factors, which play a pivotal role in inflammation. Ample evidence indicates that IKKβ mediates NF-κB activation in response to pro-inflammatory cytokines and microbial products. IKKα regulates an alternative pathway important for lymphoid organogenesis, but the role of IKKα in inflammation is unknown. Here we describe a new role for IKKα in the negative regulation of macrophage activation and inflammation. IKKα contributes to suppression of NF-κB activity by accelerating both the turnover of the NF-κB subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKKα in mice enhances inflammation and bacterial clearance. Hence, the two IKK catalytic subunits have evolved opposing but complimentary roles needed for the intricate control of inflammation and innate immunity.