The AKT protein kinase transduces signals from growth factors and oncogenes to downstream targets that control crucial elements in tumor development. The AKT pathway is one of the most frequently hyperactivated signaling pathways in human cancers. Available data are reviewed herein to support targeting the AKT kinase for cancer prevention. This review will present data to show that AKT is up-regulated in preneoplastic lesions across a broad range of target tissues, briefly describe drug development efforts in this area, and present evidence that down-regulation of AKT signaling may be a viable strategy to prevent cancer.