The NF‐κB transcription factors consist of dimeric proteins of the Rel homology family. They activate many promoters containing highly divergent κB‐site sequences. We have generated cell lines lacking individual and multiple NF‐κB proteins and used them to establish interactions between components of the NF‐κB–IκB signaling system. Functional compensation within the family of dimers was evident in knockout cell lines. Analysis of transiently transfected genes gave an impression of promiscuity that was not borne out by analysis of endogenous genes. Using TNFα as an inducer, a panel of endogenous genes showed a wide range of subunit specificities as well as highly variable kinetics of induction. Comparing the function and subunit specificity of genes with the sequence of the κB DNA‐binding site we found little correlation, indicating that NF‐κB family member specificity for endogenous promoters is not solely encoded by the κB site sequence itself.