Protein tyrosine phosphorylation plays a major role in many cellular functions implicated in cancer development and progression, but only a few of the known protein tyrosine phosphatases have yet been clearly classified as oncogenes or tumor suppressors. PTPL1 interacts with tumor-associated proteins, suggesting a link between PTPL1, the PTPN13 gene product, and tumorigenesis or cancer progression. However, the impact of PTPL1 on cancer is divided between its capacity to counteract the activity of oncogenic tyrosine kinases and its inhibitory interaction with the death receptor, Fas. In this manuscript, we review the PTPL1-interacting proteins implicated in cancer. In addition, we examine the phenotypic arguments concerning both the PTPL1/Fas interaction and the ability of PTPL1 to inhibit signaling from growth factor receptors or oncogenes with tyrosine kinase activity. Finally, we compare the alterations in expression and the genetic and epigenetic arguments supporting an oncogenic or an anti-oncogenic impact of PTPL1.