In this study, we have taken a target-centric approach to identify structural leads for the development of covalent PTP inhibitors and probes. PTPs have historically been difficult to inhibit potently and selectively, due to their highly conserved and charged active site architectures. One solution has been to pursue allosteric inhibitors, which has proven successful for SHP2. Covalent inhibition provides a different opportunity, as the long lifetimes of protein-ligand complexes often yield potent responses. A key challenge in covalent inhibitor design, however, is to optimize potency toward the desired target while mitigating off-target reactivity. Thus, we set out to understand the chemical parameters that govern covalent targeting of the conserved active-site cysteine across the classical PTP subfamily. Along these lines, there have been several noteworthy efforts towards the development of activity-based covalent probes for PTPs over the past two decades, but these efforts have focused primarily on phosphotyrosine isosteres (Figure ). Early candidates included mechanism-based quinone methide generating probes and αbromobenzylphosphonates. These molecules generally have poor membrane permeability, display nonspecific labeling, or are susceptible to solvolysis at physiological pH. Aryl vinyl sulfones and sulfonates were presented as a promising class of molecules that alleviated previous shortcomings and posed potential for further development. Here, we report that aryl vinyl sulfonates have exceedingly fast non-specific reactivity with cysteines at physiological pH, making them unsuitable for selective phosphatase labeling or inhibition in a cellular context. We present a broader exploration of chemical space beyond reactive phosphotyrosine isosteres for the covalent inhibition of tyrosine phosphatases. We assessed a variety of thiol-reactive groups and fragment scaffolds using biochemical assays on an array of purified PTPs. We combined this enzyme-targeted approach with compound reactivity assays and protein sequence/structure analyses to better understand how both ligand and protein structural features govern covalent PTP inhibition. Motivated by the lack of suitable covalent chemical tools to investigate PTPs, our studies identify lead compounds that will guide the future development of inhibitors and chemical probes for PTPs.