NFkappaB was identified 20 years ago (Sen, R., & Baltimore, D. (1986) Cell, 46, 705-716) as a nuclear factor that binds the kappa light chain enhancer in B-cells (and hence, the name NFkappaB) and was shown to play roles in innate and adaptive immune responses. More recently, its role in many other cellular processes has become apparent. Perhaps, not surprisingly, deregulated activity of the NFkappaB pathway has been observed and linked to the progression of several human ailments, including cancers. Research in the last two decades has identified the major mechanisms of activation of this pathway and has documented the roles of the key players. Over 200 physiological stimuli are known to activate NFkappaB. These include bacterial and viral products, cellular receptors and ligands, mitogens and growth factors and physical and biochemical stress inducers. The major cellular targets of NFkappaB are chemokines, immune receptors, adhesion molecules, stress response genes, regulators of apoptosis, transcription factors, growth factors, enzymes and cell cycle regulators. In addition, NFkappaB is known to be important for transcription of several viral promoter/enhancers (e.g. HIV-1 and CMV). Given that, such a large number of stimuli can activate NFkappaB, which in turn activates an equally large number of target genes, understanding how specificity generated within the framework of pleiotropic signaling is a major challenge. A thorough understanding of this would be instrumental in designing pathway specific inhibitors of NFkappaB for the treatment of specific human ailments.