The members of the Rel/NF-kappa B family of transcription factors form one of the first lines of defense against infectious diseases and cellular stress. These proteins initiate a highly coordinated response in multiple cell types that effectively counteracts the threat to the health of the organism. Conversely, disruption of the regulatory mechanisms that control the specificity and extent of this response, which results in aberrant activation of NF-kappa B, can be one of the primary causes of a wide range of human diseases. Thus, targeting NF-kappa B might lead to the development of new pharmaceutical reagents that could provide novel treatments for many inflammatory diseases and cancer.