While tyrosine phosphorylation is an important post-translational modification in cells that modulates key cellular pathways, we know relatively little about how tyrosine phosphatases are regulated in various signaling contexts. Activity-based probes that successfully target active sites of tyrosine phosphatases and report on their activities can fill in this gap. In this talk, I will show the assessment of various thiol-reactive groups for their ability to target catalytic cysteine residues with specificity. Then I will describe construction and screening of fragment-like library for their on-target and off-target reactivities, and its results. In parallel, I will give an overview of theoretical and empirical considerations for screening covalent inhibitors for their kinetic parameters. Lastly, I will discuss augmentation of compounds selected from the library to enable click chemistry for reporter group attachment for use on the whole proteome, and approaches to mass spectrometry-based proteomics, that showed specific enrichment of target proteins. These target-centric design efforts will yield new insights into the general development processes of activity-based probes or inhibitors.