Many cancers possess elevated levels of PtdIns(3,4,5)P3, the second messenger that induces activation of the protein kinases PKB/Akt and S6K and thereby stimulates cell proliferation, growth, and survival [ and ]. The importance of this pathway in tumorigenesis has been highlighted by the finding that PTEN, the lipid phosphatase that breaks down PtdIns(3,4,5)P3 to PtdIns(4,5)P2, is frequently mutated in human cancer [ and ].Cells lacking PTEN possess elevated levels of PtdIns(3,4,5)P3, PKB, and S6K activity [, ,  and ] and heterozygous PTEN+/- mice develop a variety of tumors [,  and ]. Knockout of PKBa in PTEN-deficient cells reduces aggressive growth and promotes apoptosis , whereas treatment of PTEN+/- mice with rapamycin, an inhibitor of the activation of S6K, reduces neoplasia . We explored the importance of PDK1, the protein kinase that activates PKB and S6K , in mediating tumorigenesis caused by the deletion of PTEN. We demonstrate that reducing the expression of PDK1 in PTEN+/- mice, markedly protects these animals from developing a wide range of tumors. Our findings provide genetic evidence that PDK1 is a key effector in mediating neoplasia resulting from loss of PTEN and also validate PDK1 as a promising anticancer target for the prevention of tumors that possess elevated PKB and S6K activity.