Protein S-nitrosylation, or S-nitrosylation, in general, is a redox-regulated posttranslational mechanism that has gained momentum over the years as a double-edged sword with unprecedented versatility in playing crucial roles in multiple debilitating disorders or disease conditions, including cancer. The prominence of this reversible redox modification upon the covalent attachment of NO/NO moiety (N2O3; autoxidation of NO)/NO bearing compounds (nitrous acid, metal nitrosyl complexes, NO donors, and peroxynitrite) to sulfhydryl (thiol) groups is highlighted by the fine-tuning of the S-nitrosylation and S-denitrosylation-based redox switch, which markedly hints toward its cellular prudence in basal and stimulus-induced (in the presence of nitrosative stressors) conditions, thus extending the credibility of NO-based research in dodging abrogated redox equilibrium in disease states. S-nitrosylation of specific endogenous caspase-like cysteine proteases (mainly, caspases 3, 8, and 9) leads to the dysregulation or inhibition of their proteolytic activity and further downstream signaling cascade leading to apoptosis per se, which can differentially influence oncogenic potential and/or cancer prevention, depending on the specificity of the targeted substrate protein and NO transport machinery/delivery system in healthy and cancer cells; reversibility or S-denitrosylation of caspases is efficiently ensured by two ubiquitous redox checkpoint systems, thioredoxin and lipoic acid, that aid in counteracting any nitro-oxidative shift in caspase thiol status. Knowledge and understanding of these redox-based protein posttranslational mechanisms regulating apoptotic signaling cascades may pave the way for strategizing novel redox-based therapeutic regimens to jeopardize cellular homeostasis, cell growth, and survivability in cancer cells.