The diversity of activators and targets of the NF-kappaB transcription factor family demands that there be regulatory mechanisms in place to control the specificity with which genes under their control are induced. In part this can be achieved through selective induction of different NF-kappaB subunits and through co-operative interactions with heterologous DNA-binding proteins and co-activators. Recent work from our laboratory indicates another critical mechanism regulating NF-kappaB. We find that the RelA(p65) NF-kappaB subunit does not always function as an inducer of gene expression, but under certain circumstances can be programmed to actively repress these same target genes. This repressor form of NF-kappaB appears to be induced by distinct, atypical pathways of activation and also through the action of some tumor suppressors. The identification of these pathways not only allows a reinterpretation of NF-kappaB function in normal cells and during tumorigenesis but could also have implications for both traditional and NF-kappaB based cancer therapy.