The proto-oncogene protein kinase B (PKB), also known as c-Akt, is a central player in a signaling pathway of which many components have been linked to tumorigenesis. Active forms of PKB as well as of its upstream activator phosphatidylinositol 3-kinase (PI3K) have been found to be responsible for the transforming activities of certain viruses, and the negative regulator of this pathway, PTEN, is a tumor suppressor. The identification of particular downstream targets of PKB has provided us with new insights into the possible mechanism of PI3K/PKB-mediated tumorigenicity. Recently a subfamily of Forkhead transcription factors was identified as additional targets for PI3K/PKB signaling. This review discusses the studies that have led to this conclusion and the possible implications of this finding for our understanding of how PI3K/PKB activity could lead to oncogenesis.