Cysteine in proteins can perform diverse functions owing to its intrinsically high nucleophilicity. The development of cysteine-specific electrophiles, in combination with state-of-the-art chemoproteomics, have greatly expanded the ligandable and druggable space in the human proteome. In addition, protein cysteines are subjected to diverse redox chemistry in cells. Oxidation of nucleophilic cysteinyl thiols to amphoteric sulfenic acids can abolish their reactivity toward electrophiles, yet chemical tools to modulate such redox functionality of cysteine are underdeveloped. Here we report a large-scale quantitative analysis of nucleophilic fragment compounds target-profiled against the human sulfenylome .