T he forkhead box O (Foxo) subfamily of transcription factors regulates expression of genes important for many cellular processes, ranging from initiation of cell cycle arrest and apoptosis to induction of DNA damage repair. Invertebrate Foxo orthologs such as DAF-16 also regulate longevity. Cellular responses inducing resistance to ROS are important for cellular survival and organism lifespan, but until recently, mammalian factors regulating resistance to oxidative stress have not been well characterized. Marinkovic and colleagues demonstrate in this issue of the JCI that Foxo3 is specifically required for induction of proteins that regulate the in vivo oxidative stress response in murine erythrocytes (see the related article beginning on page 2133). Their work offers the interesting hypothesis that in so doing, Foxo3 may regulate the lifespan of red blood cells, and underlies the importance of understanding the direct targets of this transcription factor and its regulation.