The Protein Tyrosine Phosphatase (PTP) family contains not only several promising drug targets, such as PTP1B, but also proteins that are essential to cell development and survival. The availability of sequences and representative structures for the PTP family allows better identification of anti-targets, closely related family members likely to cross-react with directed inhibitors. Eight PTP subfamilies, classified by active site information and overall PTP catalytic domain structure similarity, are reviewed here: 1) the tyrosine-specific PTPs, 2) the dualspecificity PTPs, 3) the cdc25 subclass; 4) the Pten subclass; 5) the myotubularins, 6) the PRL subclass, 7) the low molecular weight PTPs, and 8) the newly defined cdc14 subclass. PTP subfamily classification and structure information can be incorporated into design strategies aimed at identifying potent and selective small molecule inhibitors. The accumulating inhibition data for compounds screened against panels of PTPs is reviewed. The in vitro data can yield clues to specificity so that individual subfamilies can be matched with effective scaffolds to jumpstart lead design and reduce false starts.