PTEN is an obligate haplo-insufficient tumor suppressor gene and is commonly mutated in a large number of cancers. It negatively regulates intracellular levels of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. PTEN mutations have been reported in up to 19% of gastric cancers. Germline mutations in PTEN are also responsible for Cowden disease, a rare autosomal dominant multiple-hamartoma syndrome. Patients with Cowden disease can have gastric polyps, but a possible association with gastric cancer needs further study. Inactivation of PTEN is shown to be closely associated with tumor progression and metastases. Clinical trials using PI3K-beta inhibitor are available for patients with PTEN-deficient tumors.