The Stamler lab has pioneered the field of S-nitrosylation-mediated protein control, a fundamental mechanism of cellular regulation and signaling that operates across phylogeny and cell type. S-nitrosylation subserves physiology essential for mammalian life and has been implicated in diverse diseases, ranging from heart and lung disorders to neurodegenerative diseases and cancer. The process of S-nitrosylation entails an oxidative modification of cysteine (Cys) residues by nitric oxide (NO) to form S-nitrosothiols (SNOs) that regulate the activity, interactions, stability or subcellular localization of proteins in all functional categories. S-nitrosylation is carried out by a multiplex machinery involving three classes of enzymes: (1) NO synthases that generate NO, (2) SNO synthases that conjugate NO to Cys, and (3) transnitrosylases that transfer the NO group to protein substrates. Additional enzymes, termed denitrosylases, mediate SNO removal from proteins and thereby serve as major determinants of steady-state levels of S-nitrosylation. Denitrosylases are categorized as low-molecular-weight (including S-nitroso-glutathione and S-nitroso-CoA reductases) or high-molecular weight (e.g. thioredoxin-related proteins), reflecting mechanism-based denitrosylation by small molecules and proteins, respectively. Identification of novel S-nitrosylases and denitrosylases across model systems, animals, and humans is a key focus of the lab, with the aim of delineating SNO-regulated pathways and therapeutic targets. We are currently developing first-in-class agents that modulate S-nitrosylation in a tissue- and target-specific manner, promising new treatments for human disease.