ROS and RNS such as O₂^–, H₂O₂, and NO are generated in cells by the regulated activity of dedicated enzymes such as NADPH oxidases (NOX) and NOS and by additional sources such as mitochondria. NO is efficiently converted into low-molecular-weight SNOs (e.g., S-nitrosoglutathione [GSNOs]), which convey the large part of NO bioactivity. NO can react with O₂^– to produce ONOO^–, a potent oxidant and nitrating agent. ROS and RNS play various roles in both homeostatic and pathological processes. The physiological roles of H₂O₂ and NO and SNO are principally mediated through the S-oxidation or S-nitrosylation of protein Cys residues (RSH) to form sulfenic acids (RSOH), disulfides (RSSR), and protein S-nitrosothiols (RSNO), thereby altering protein structure and function. GSH and Trx and associated redox enzymes, such as glutaredoxin (Grx), reverse these thiol modifications. Oxidized GSH (GSSG) and oxidized Trx (Trx-S₂) are reduced by GSH reductase (GR) and TrxR, respectively, at the expense NADPH oxidation. The thiol-reducing activity of GSH and Trx is of key importance in maintaining the enzymatic activity of members of the peroxiredoxin (Prx) and GSH peroxidase (Gpx) enzymes, which remove peroxides. Additionally, GSH acts together with GSH S-transferases (GST enzymes) to detoxify various xenobiotics, and Trx acts with methionine sulfoxide reductases to repair oxidized methionines. GSNO is metabolized by the NADH-dependent GSNOR, which thereby shifts the cellular equilibrium to disfavor protein SNOs, while Trxs and TrxRs denitrosylate proteins directly. GSNHOH, N-hydroxy sulfenamide.