The Foxo family of transcription factors belongs to the winged helix or forkhead box class of transcription factors. Invertebrates possess 1 Foxo gene, termed daf-16 in the worm and dFoxo in the fly. Mice and humans possess 4 Foxo members: Foxo1, Foxo3, Foxo4, and Foxo6. Foxo1, Foxo3, and Foxo4 are highly related homologs with overlapping patterns of expression and transcriptional activities. The Foxo protein family is regulated primarily by post-translational modifications, including phosphorylation, acetylation, monoubiquitination, and polyubiquitination. These various modifications control subcellular localization and protein levels, as well as efficacy of DNA binding and transcriptional activity. Most notably, Foxo1, Foxo3, and Foxo4 have 3 conserved amino acids that are targets for phosphorylation by Akt or serum/glucocorticoidregulated kinase (SGK). Phosphorylation at these sites leads to nuclear exclusion of the transcription factor. Foxos have been shown to play a role in many physiological processes, including the control of cell proliferation and survival, cell cycle progression, DNA repair, oxidative stress resistance, energy metabolism, and cell differentiation. Unrestrained Foxo activity can result in cellular senescence, autophagy, and atrophy and can promote a catabolic state. Both Foxo3and Foxo4-null mice are viable. In contrast, mice that are null for Foxo1 are embryonic lethal at E11 because of impaired vasculogenesis. Thus, Foxo1 has a specific role in vascular development, which cannot be compensated for by other Foxo family members. Foxo1 is expressed in multiple cell types and tissues during development, including endothelial cells, smooth muscle cells, neural crest cells, cardiomycoytes, adipose tissue, somites, branchial arches, and trigeminal ganglia. In contrast to the embryonic knockout, widespread somatic deletion of Foxo1 in adult tissues predisposes to the development of vascular bed–specific hemangiomas, an effect that is accentuated by combined deletion of Foxo3 and Foxo4. Molecular Medicine