Isothiazolidinones are a rare but potentially important chemical moiety in biochemistry. We report the identification of several thiol, phosphinate,and carbon nucleophiles that form covalent adducts by addition to the sulfenamide sulfur. This reduction is selective for isothiazolidinonesover similar peptide disulfides. We synthesized a coumarin-based thioacid nucleophile which shows a marked fluorescence increase afteraddition to an isothiazolidinone sulfenamide bond.