The PTEN tumor suppressor was discovered by its homozygous deletion and other mutations in cancer. Since then, PTEN has been shown to be a non-redundant, evolutionarily conserved phosphatase whose function affects diverse cellular progresses such as cell cycle progression, cell proliferation, chemotaxis, apoptosis, aging, muscle contractility, DNA damage response, angiogenesis and cell polarity. In accordance with its ability to influence multiple crucial cellular processes, PTEN has a major role in the pathogenesis of numerous diseases such as diabetes, autism and almost every cancer examined. This review will discuss the diverse ways in which PTEN signaling is modified in cancer, and how these changes correlate with and might possibly affect the action of targeted chemotherapy.