Inspired by a recent resurgence in covalent inhibitors for challenging therapeutic targets, we set out to explore the chemical parameters required for active site covalent inhibition of phosphatases. While covalent ligands for tyrosine phosphatases have been previously identified, most studies have focused on phosphotyrosine isosteres and a handful of reactive warheads. These past efforts have identified promising molecules but have not yielded significant drug leads or probes that are compatible with mass spectrometry proteomics. As an alternative approach, we explored a broad range of electrophiles and compound structures that deviate from previously characterized chemotypes. Our focused screening yielded a series of guiding principles for future tyrosine phosphatase inhibitor and probe design: (1) we have determined which of the common electrophilic warheads are compatible with tyrosine phosphatase inhibition and identified chloroacetamide as useful starting point for ligand design, (2) our study points to thiazoles and isoxazoles as unique core scaffolds for tyrosine phosphatase inhibitors, and (3) our data show that aliphatic scaffolds and bulky tertiary amide-derived electrophiles have uniquely low potency against all phosphatases that we tested.