Nuclear Factor-Kappa B (NF-κB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF- κB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-κB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasomedependent degradation of its inhibitory protein (IκB), resulting in free NF-κB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-κB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-κB. In this article, we present a critical review of the pharmacological agents that have been studied as inhibitors of NF-κB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of κB DNA recognition and binding. Beginning with a general overview of NF-κB pathway and several possibilities of chemical interventions, the significance of redoxregulation in NF-κB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-κB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-κB-inhibitors.