Receptor protein tyrosine phosphatases (RPTPs) are involved in a broad list of cellular, developmental, and physiological functions. Altering their expression leads to significant changes in protein phosphorylation linked to a growing list of human diseases, including cancers and neurological disorders. In this issue of , Qian and colleagues (pp. 743-759) present the identification of a monoclonal antibody targeting PTPRD extracellular domain-inducing dimerization and inhibition of the phosphatase activities, causing the proteolysis of dimeric PTPRD by a mechanism involving intracellular degradation pathways. Their study supports the potential of modulating PTPRD via its extracellular domains. This opens a new framework in the clinical manipulation of PTPRD and its closely related family members.