The FoxO family of Forkhead transcription factors functions at the interface of tumor suppression, energy metabolism, and organismal longevity. FoxO factors are key downstream targets of insulin, growth factor, nutrient, and oxidative stress stimuli that coordinate a wide range of cellular outputs. FoxO-dependent cellular responses include gluconeogenesis, neuropeptide secretion, atrophy, autophagy, apoptosis, cell cycle arrest, and stress resistance. This review will discuss the roles of the mammalian FoxO family in a variety of cell types, from stem cells to mature cells, in the context of the whole organism. Given the overwhelming evidence that the FoxO factors promote longevity in invertebrates, this review will also discuss the potential role of the FoxO factors in the aging of mammalian organisms.