PTEN is an obligate haplo-insufficient tumor suppressor gene and is mutated in a large number of cancers. It encodes a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/mTOR signaling pathway. PTEN mutations are loss-of-function mutations and occur in 1% to 5% of ccRCCs. Recent studies suggest that only biallelic loss, resulting from deletion and/or inactivating mutations, is associated with an adverse outcome in ccRCCs. Whether PTEN alterations predict for responsiveness to mTORC1 inhibitors is less certain at this time.