Updated project metadata. Catechol estrogens (CEs) are metabolic electrophiles that actively undergo covalent interaction with cellular proteins, influencing molecular function. There is no feasible method to identify their binders in a living system. Herein, we developed a click chemistry-based approach using ethinylestradiol(EE2) as the precursor probe coupled with quantitative proteomics to identify protein targets of CEs and classify their binding strengths.