Protein tyrosine phosphorylation is one of the key mechanisms involved in signal transduction pathways. This modification is regulated by concerted action of protein tyrosine phosphatases and protein tyrosine kinases. Deregulation of either of these key regulators lead to abnormal cellular signaling, which is largely associated with human pathologies including cancer. Although the role of protein tyrosine kinases in cancer is well established, less is known about the involvement of protein tyrosine phosphatases in carcinogenesis and tumor progression. Moreover, several inhibitors targeting protein tyrosine kinases have demonstrated their value in cancer treatment, while interest in protein tyrosine phosphatases as a target for treatment has risen more recently. In this review we describe the progressive efforts and challenges concerning the development of drugs targeting phosphatases as promising novel cancer therapies. We focus on two key regulatory SH2 domain-containing phosphatases, SHP-1 and SHP-2 and one of their substrates, signal regulatory protein alpha. Since SHPs have been linked to many different malignancies, protein tyrosine phosphatases could offer a great spectrum of new, targeted drugs.