Recent studies find striking similarities between p53 and the FOXO family of forkhead transcription factors. Both transcription factors can be posttranslationally modified, for example, by acetylation and phosphorylation. They regulate a number of genes in common. Upregulation of either p53 or FKHRL1 leads to cell cycle arrest or apoptosis, depending on cellular context and type of stress. While these findings suggest that p53 and FOXO may parallel in their functions, our recent report demonstrates cross talk between these two transcription factors in vivo. Since both p53 and FOXO have been described as potential drug targets in cancer therapy, we believe understanding their functional interactions as well as the signaling pathways involved will be important to direct their clinical application.