A myriad of unrelated exogenous or endogenous agents that represent a threat to the organism are capable of inducing NF-kappaB activity, including viral infection, bacterial lipids, DNA damage, oxidative stress and chemotherapuetic agents. Likewise, NF-kappaB regulates the expression of an equally diverse array of cellular genes. These findings are indicative of the widespread significance of NF-kappaB as a mediator of cellular stress. Remarkably, the NF-kappaB pathway displays the capacity to activate, in a cell- and stimulus-specific manner, only a subset of the total repertoire of NF-kappaB-responsive genes. The seemingly promiscuous nature of NF-kappaB activation poses a regulatory quagmire as to how specificity is achieved at the level of gene expression. The review will summarize recent findings and explore how they further our understanding of the mechanism by which stimulus-specific activation of NF-kappaB is achieved in response to cellular stress.