A unique feature of our study is the parallel characterization of covalent inhibition for several members of the classical protein tyrosine phosphatase family. This comparative approach revealed unexpected trends in reactivity and selectivity across different phosphatases, even for a relatively small compound library comprised entirely of fragment-like molecules. Most notably, we observed that tyrosine phosphatases with high catalytic activity are difficult to inhibit covalently, and we found that the closely related enzymes SHP1 and SHP2 have distinct fragment preferences. Our study provides new insights into sequence-structureactivity relationships in PTPs by analyzing these enzymes through the lens of covalent inhibition. Altogether, we anticipate that our findings will guide future ligand design efforts and will fuel new biophysical and biochemical investigations into tyrosine phosphatase activity and regulation.