A myriad of unrelated exogenous or endogenous agents that represent a threat to the organism are capable of inducing NF-κB activity, including viral infection, bacterial lipids, DNA damage, oxidative stress and chemotherapuetic agents. Likewise, NF-κB regulates the expression of an equally diverse array of cellular genes. These findings are indicative of the widespread significance of NF-κB as a mediator of cellular stress. Remarkably, the NF-κB pathway displays the capacity to activate, in a cell-and stimulus-specific manner, only a subset of the total repertoire of NF-κB-responsive genes. The seemingly promiscuous nature of NF-κB 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-κB is achieved in response to cellular stress.