Sphingolipid metabolites regulate cell proliferation, migration, and stress responses. Alterations in sphingolipid metabolism have been proposed to contribute to carcinogenesis, cancer progression, and drug resistance. We identified a family of natural sphingolipids called sphingadienes and investigated their effects in colon cancer. We find that sphingadienes induce colon cancer cell death in vitro and prevent intestinal tumorigenesis in vivo. Sphingadienes exert their influence by blocking Akt translocation from the cytosol to the membrane, thereby inhibiting protein translation and promoting apoptosis and autophagy. Sphingadienes are orally available, are slowly metabolized through the sphingolipid degradative pathway, and show limited short-term toxicity. Thus, sphingadienes represent a new class of therapeutic and/or chemopreventive agents that blocks Akt signaling in neoplastic and preneoplastic cells. [Cancer Res 2009;69(24):9457–64]