PTEN is a tumor suppressor gene, located on chromosome 10q23. It encodes a lipid and protein phosphatase that negatively regulates the PI3K/AKT/mTOR pathway. Cancer-associated alterations in this gene often result in loss of PTEN protein and upregulation of the PI3K/AKT/mTOR pathway. Germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome while somatic mutations are also known to occur in multiple malignancies, particularly as an early event in the development of endometrial cancer. PTEN gene sequence abnormalities are highly variable in type (frameshifts, point mutations) and can occur throughout all 9 exons. Germline mutations of PTEN, found in Cowden’s syndrome, are associated with an increased risk of endometrial cancer. Somatic mutations of PTEN occur in up to 50% of complex atypical hyperplasia and type I endometrial adenocarcinomas. Clinical trials assessing the efficacy of PI3K and mTOR inhibitors in PTEN loss are being explored.