Members of the class O of forkhead box transcription factors (FoxO) have important roles in metabolism, cellular proliferation, stress tolerance and probably lifespan. The activity of FoxOs is tightly regulated by post-translational modifications, including phosphorylation, acetylation and ubiquitylation. Several of the enzymes that regulate the turnover of these post-translational modifications are shared between FoxO and p53. These regulatory enzymes affect FoxO and p53 function in an opposite manner. This shared yet opposing regulatory network between FoxOs and p53 may underlie a 'trade-off' between disease and lifespan.