The phosphatase and tensin homologue PTEN was originally identified as a tumor suppressor. In the CNS, mutation or inactivation of PTEN is best known for playing a tumorigenic role in the molecular pathogenesis of glioblastoma. However, recent studies show that PTEN is associated with several brain diseases other than cancer, suggesting a broader role of PTEN in CNS pathophysiology. Here, we review the evidence for the crucial involvement of PTEN in neuronal injury as well as in neurological and psychiatric disorders, and discuss the potential of PTEN as a molecular target for the development of a novel CNS therapeutic strategy.