Protein tyrosine phosphatases (PTPs) have emerged as a new and promising class of signaling targets, since the discovery of PTP1B as a major drug target for diabetes and obesity. Blocking individual PTPs results in the activation of specific tyrosine phosphorylation events, but matching PTPs with such pathways and therapeutic indications is a complex undertaking. The history of PTP1B shows that its unusual knockout phenotype and observations with generic and antisense inhibitors in vivo, but not its classical molecular biology, triggered the rapid development of inhibitors that are today being developed for the clinic.