Aspate of recent discoveries indi-cates that the study of protein S-nitrosylation is rapidly leaving its salad days behind. S-nitrosylation, the formation of S-nitrosothiol (SNO) by covalent addition to cysteine (Cys) residues of a nitric oxide (NO) moiety (formally as NO+), has been shown to regulate in intact cells the function of a broad spectrum of proteins (1). Important recent findings include demonstrations of major roles for S-nitrosylation in vesiclemediated insulin release (2), in protein processing associated with the neurodegeneration of Parkinson’s disease (3), and in the essential mechanisms of vectorial membrane trafficking (4). In this issue of PNAS, Reynaert et al.(5) lend a hand in the unveiling of S-nitrosylation as it operates in cellular context by elucidating a role in regulating NF-κB. NF-κB denotes a ubiquitous family of transcription factors that transduce a wide range of noxious or inflammatory stimuli into the coordinated activation of multiple genes, including those coding for cytokines, cytokine receptors, adhesion molecules, and antiapoptotic proteins (6). NF-κB thus serves as a critical element in immune and inflammatory responses and in cell survival and proliferation, with central roles in host defense and in acute and chronic disorders of immune function. NF-κB can upregulate the expression of all major NO synthases (nNOS, iNOS, and eNOS). It is well established that NF-κB is complexed with and sequestered in the cytoplasm by inhibitory IκB (inhibitor of NF-κB) proteins and that many activating stimuli induce phosphorylation of IκB by the IκB-kinase complex (IKKα, IKKß, and IKK), initiate IκB ubiquitinylation and degradation by means of the 26S proteasome, and allow translocation of NF-κB to the nucleus (6). The molecular cascades that run through NF-κB present multiple loci at which oxidativenitrosative modification could potentially modulate signal transduction, but the role of NF-κB and its attendant proteins in physiological redox responsivity has remained controversial, principally because of the lack of evidence for their direct redox-based modification in the context of physiological signal transduction. The prototype of the NF-κB family is the p50p65 heterodimer expressed constitutively in most mammalian cells. S-nitrosylation of NF-κB in vitro or in intact cells, either with exogenous NO or consequent upon induction of iNOS, inhibits NF-κB-dependent DNA binding, promoter activity, and gene transcription (7, 8). Analysis in vitro indicated that p50 is S-nitrosylated at Cys-62, which is located in the N-terminal DNA binding loop within the Rel-homology domain. Cys-62 is conserved in other Rel-homology domain-containing proteins that can serve as NF-κB subunits, including p65, p52, p100, p105, and c-Rel. In addition, it was shown that treatment of intact cells with either NO or SNO significantly enhances tumor necrosis factor (TNF)-αinduced apoptosis in a cGMP-independent fashion and that this facilitation may reflect not only reduced DNA-binding affinity of NF-κB but also decreased IκB degradation, thereby preventing the nuclear translocation of NF-κB (9). Thus, it appeared that S-nitrosylation (of as yet unidentified elements) might also regulate the phosphorylation-dependent proteasomal targeting of IκB. The central finding of Reynaert et al.(5) is that S-nitrosylation of the catalytic IKKß subunit of the IKK complex inhibits IκB phosphorylation. It is further shown that TNF-α activation of IKKß is coordinated with denitrosylation.