IκB kinase-α and -β (IKK-α and IKK-β), the catalytic subunits of the IKK complex, phosphorylate IκB proteins on specific serine residues, thus targeting IκB for degradation and activating the transcription factor NF-κB. To elucidate the in vivo function of IKK-β, we generated IKK-β-deficient mice. The homozygous mouse embryo dies at ∼14.5 days of gestation due to liver degeneration and apoptosis. IKK-β-deficient embryonic fibroblasts have both reduced basal NF-κB activity and impaired cytokine-induced NF-κB activation. Similarly, basal and cytokine-inducible kinase activities of the IKK complex are greatly reduced in IKK-β-deficient cells. These results indicate that IKK-β is crucial for liver development and regulation of NF-κB activity and that IKK-α can only partially compensate for the loss of IKK-β.