A handful of protein tyrosine phosphatases are well-characterized and have been identified as potential therapeutic targets for the treatment of cancer, metabolic diseases, and immune disorders. Nevertheless, the biological roles and regulatory mechanisms of most members of this enzyme family remain poorly characterized. Given their promise as therapeutic targets and the need for more phosphatase-focused discovery biology, there have been extensive efforts to design new chemical tools for tyrosine phosphatases. These can be broadly classified into: (1) non-covalent orthosteric and allosteric inhibitors that serve as both chemical probes and lead compounds for drug discovery, (2) fluorescent substrates that report on the activity of tyrosine phosphatases in cells, and (3) covalent probes to profile tyrosine phosphatase activity and regulation in the proteome. On the one hand, the design of drug molecules and enzyme-specific reporters requires selectivity for individual phosphatases. On the other hand, probes for activity-based profiling of tyrosine phosphatases would ideally be family-wide, and the identification of labeled phosphatases would be enabled by mass spectrometry proteomics. Tackling either of these goals requires a comprehensive view of the small molecule chemotypes that are compatible with tyrosine phosphatases, as well as a deep understanding of the features of tyrosine phosphatases that govern their selective ligandability.