To ensure a sufficient energy supply necessary to undergo differentiation, mesenchymal stem cells (MSCs) undergo a metabolic switch, lowering glycolysis and increasing mitochondrial respiration. As a consequence of increased mitochondrial metabolism the levels of endogenous reactive oxygen species (ROS) rise. Here Catalina Gomez-Puerto together with Magdalena Lorenowicz have characterized the anti-oxidant role of the Forkhead transcription factor FOXO3A in controlling ROS levels in human MSCs during osteogenic differentiation. Their findings support a model where MSC differentiation activates a FOXO-mediated autophagy program to cope with elevated ROS levels resulting from the increased osteoblast mitochondrial respiration. These new molecular insights into osteoblast generation provide an important contribution to our understanding of bone physiology This work has been accepted for publication in Autophagy.