Protein tyrosine phosphatases (PTPs) constitute a large family of enzymes that can exert both positive and negative effects on signaling pathways. They play dominant roles in setting the levels of intracellular phosphorylation downstream of many receptors including receptor tyrosine kinases and G protein-coupled receptors. As observed with kinases, deregulation of PTP activity can also contribute to cancer. This review will examine a broad array of PTP family members that positively affect oncogenesis in human cancer tissues. We will describe the PTP family, their biological significance in oncology, and how recent progress is being made to more effectively target specific PTPs. Finally, we will discuss the therapeutic implications of targeting these oncogenic PTPs in cancer.