Squamous cell carcinomas and several other cancers have been found to exhibit microarray expression profiles that include genes related to nuclear factor (NF)-kappaB, a signal activated transcription factor that is evolutionarily important in regulating early response gene programs to injury and infection. Inhibition of NF-kappaB by expression of a dominant negative signal phosphorylation site mutant of inhibitor-kappaB, IkappaBalphaM, under a tetracycline inducible promoter, established the role of NF-kappaB as an essential molecular switch modulating multiple genes important in the malignant phenotype. Bioinfomatic analysis of the promoter and coding region of IkappaBalphaM-modulated genes has enabled identification of new candidates with and without known NF-kappaB related motifs for validation and functional studies of their relationship to NF-kappaB. These studies illustrate how microarray data can be used to generate a hypothesis regarding regulation of genes by a specific signal transcription factor, and how genetic mutants and bioinformatic analysis can be used to analyze the relative importance of the regulatory molecule to expression of genes involved in the malignant phenotype.