Covalent chemical probes and inhibitors for tyrosine phosphatases have historically been challenging to develop. We report the characterization of diverse cysteine-reactive electrophiles and fragment-like scaffolds as covalent ligands for tyrosine phosphatases. Our investigation reveals chemical constraints for tyrosine phosphatase covalent inhibitor design and sheds light on the structural features of phosphatases that govern their susceptibility to covalent inhibition.