Protein tyrosine phosphatases (PTPs) are emerging new targets for drug discovery. PTPs and protein tyrosine kinases (PTKs) maintain cellular homeostasis through opposing roles: tyrosine O-dephosphorylation and -phosphorylation, respectively. An imbalance in the phosphorylation equilibrium results in aberrant protein signaling and pathophysiological conditions. PTPs have historically been considered 'undruggable', in part due to a lack of evidence defining their relationship to disease causality and a focus on purely competitive inhibitors. However, a better understanding of protein-protein interfaces and shallow active sites has recently renewed interest in the pursuit of allosteric and orthosteric modulators of targets outside the major druggable protein families. While their biological mechanism of action still remains to be clarified, PTP4A1-3 (also referred to as PRL1-3) are validated oncology targets and play an important role in cell proliferation, metastasis, and tumor angiogenesis. In this Digest, recent syntheses and structure-activity relationships (SAR) of small molecule inhibitors (SMIs) of PTP4A1-3 are summarized, and enzyme docking studies of the most potent chemotype are highlighted. In particular, the thienopyridone scaffold has emerged as a potent lead structure to interrogate the function and druggability of this dual-specificity PTP.