Sulfenyl halides have been found t o be specific, mild reagents for modification of tryptophan and cysteine residues of polypeptides and proteins in acidic media, such as acetic acid or formic acid. With hydrolysis-resistant halides, like 2-nitro-(NPS-C1) and 2,4-dinitrophenylsulfenyl chloride (DNPS-CI), the reaction can be carried out in aqueous solvents such as 30-50% acetic acid. Tryptophan is smoothly converted by reaction with sulfenyl halides into a derivative with a thioether function in the 2 position of the indole nucleus, and cysteine to an unsymmetrical disulfide. The high specificity of the reaction toward tryptophan and cysteine was established after quantitative recovery on the amino acid analyzer of the other amino acids, after 15-hr reaction with NPS-CI in acetic acid. As a further check, ribonuclease A, a protein containing neither tryptophan nor cysteine, was allowed to react with 20 equiv of NPS-CI in SOP;: acetic acid. The protein was recovered