Rel/NF-kappaB transcription factors have been implicated in regulating a wide variety of genes important in cellular processes that include cell division, cell survival, differentiation and immunity. Here genetic models in which various Rel/NF-kappaB and IkappaB proteins have either been over-expressed or deleted in mice will be reviewed. Although expressed fairly ubiquitously, homozygous disruption of individual Rel/NF-kappaB genes generally affects the development of proper immune cell function. One exception is rela, which is essential for embryonic liver development. The disruption of genes encoding the individual subunits of the IkappaB kinase, namely IKKalpha and IKKbeta, has demonstrated that IKKbeta transmits the response to most common NF-kappaB inducing agents, whereas IKKalpha has an unexpected role in keratinocyte differentiation. Future studies will no doubt focus on the effect of multiple gene disruptions of members of this signaling pathway, on tissue-specific disruptions of these genes, and on the use of these mice as models for human diseases.