Nuclear factor (NF)-κB proteins play crucial roles in immune responses and cellular survival. Activation of NF-κB is mediated by the IκB kinase (IKK) complex, which is composed of two kinases, IKK1 and IKK2, and a regulatory subunit termed NF-κB essential modulator (NEMO). IKK2- and NEMO-deficient mice die at early embryonic stages. We therefore used conditional gene targeting to evaluate the role of these proteins in B cells in adult mice. B lineage–specific disruption of either IKK signaling by deletion of NEMO, or of IKK2-specific signals by ablation of IKK2 activity leads to the disappearance of mature B lymphocytes. We conclude that maintenance of mature B cells depends on IKK-mediated activation of NF-κB.