The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene is mutated in a wide range of malignancies and recent studies have demonstrated that PTEN prevents tumorigenesis through multiple mechanisms. PTEN functions as a plasma-membrane lipid phosphatase that antagonizes the PI3K (phosphoinositide 3 kinase)-AKT pathway. PTEN physically and genetically interacts with the central genome guardian p53. PTEN also associates with the centromeric protein CENP-C to maintain centromere integrity and suppresses chromosomal instability from DNA double-strand breaks (DSBs) through transcriptional regulation of Rad51 (radiosensitive yeast mutant 51). Moreover PTEN controls the growth and proliferation of haematopoietic stem cells (HSC) and restrains cells from leukemia in an mTOR (mammalian target of rapamycin) dependent manner. Thus, restoring PTEN functions in cancer cells directly or indirectly holds great promise for cancer therapy.