Protein phosphorylation and dephosphorylation are complex enzymatic reactions that are performed by the concerted action of protein kinases and phosphatases, respectively. Deregulation of such coordination due to loss or gain of a single component of the process can result in disease conditions that include, but are not limited to, neoplastic transformation, developmental, autoimmune, and metabolic disorders. Unlike many protein tyrosine kinases that function as oncoproteins, protein tyrosine phosphatases (PTPs) could impart positive or negative effect on cell proliferation. Although past studies have suggested a potential role for PTPs in cancer, the molecular mechanisms of the altered activity/level of these enzymes and the pathological manifestations of these modifications in diseases, particularly in cancer, have not been critically analyzed. This chapter is a comprehensive survey of the alterations of PTPs and the implications of the growth, proliferation, and apoptosis phenotypes attributable to the altered function of this family of phosphatases in cancer. Further, the potential applications of different therapeutic approaches to rectify the adverse effects of alterations in expression of the phosphatase genes and of the phosphatase activity in cancer are discussed.