FOXO1, also known as FKHR or ForkHead in Rhabdomyosarcoma, is a 70 kDa protein which is a ubiquitously expressed member of a subfamily of the forkhead homeotic gene family of transcription factors and shuttles between the cytoplasm and nucleus. FOXO transcription factors are key players of cell fate decisions, metabolism, stress resistance, tumor suppression and are regulated by growth factors, oxidative stress or nutrient deprivation. In insulin-responsive tissues, stress or nutrient abundance triggers phosphorylation by PKB/AKT, blocking nuclear translocation and activity. Genetic mutations involving FOXO1A are a cause of alveolar rhabdomyosarcoma (RMS2). Recent studies link the anti-tumor activity of FOXO1 and the process of autophagy.