Accumulated evidence indicates that, by the phosphorylation of its physiological substrates, Akt promotes cell survival, proliferation and angiogenesis. While a number of Akt targets have been identified, the mechanism by which Akt regulates cell survival and growth and induces malignant transformation still remains elusive. During the last 5 years, I have shown that AKT1 cross-talks with Src/Stat3 pathway. AKT1 is a direct target gene of Stat3. Protein/mRNA levels and promoter activity of AKT1 are significantly induced by constitutively active Src and Stat3. Knockdown of Stat3 or dominant-negative Stat3 reduced AKT1 expression induced by constitutively active Src. Blockage of AKT1 expression largely reduced Stat3 function in cell survival and angiogenesis. Furthermore, I have shown that proapoptotic protein 24p3 is a major target of Akt to mediate IL3 signaling in hematopoietic cells. Forkhead transcription factor FOXO3a directly binds to and activates 24p3 promoter leading to expression of 24p3 in response to IL3 withdrawal. Akt phosphorylates FOXO3a and inhibits its action toward 24p3. Finally, I have identified a novel transcription factor TZP that interacts with Akt and p53. Expression of TZP inhibits cell growth and survival and induces both G1 and G2/M cell cycle arrest. TZP directly binds to the p53 promoter and induces p53 transcription. In addition, TZP interacts with p53 and prevents p53 from Mdm2-mediated degradation. In response to genotoxic stress, both TZP and p53 were upregulated and knockdown of TZP reduced p53 expression. Akt phosphorylated TZP resulting in its translocation from the nucleus into the cytoplasm, and thus inhibits TZP function. These data indicate that Akt induced by STAT3 confers oncogenesis through inhibition of the transcription factors.