FoxO (forkhead box O) transcription factors, one of the main downstream mediators of PI3K (phosphatidylinositol-3 kinase)/Akt [also known as PKB (protein kinase B)] signal transduction pathway, play an important role in modulating cellular homoeostasis. Recent studies have revealed the significance of FoxO in bone, the interaction of FoxO with β-catenin, along with mechanical stress-induced inactivation of FoxO via PI3K/Akt. We hypothesize that FoxO is a novel participant in mechanotransduction of bone cells in a PI3K/Akt-dependent way. After describing downstream targets of FoxO, we speculate that FoxO would be involved in the positive effects of mechanical stimulation on bone cells directly through its target genes. We have also concisely represented the cross-talk between ROS (reactive oxygen species) and Wnt/β-catenin pathway, which leads us to hypothesize that the inhibition of FoxO caused by mechanical stress acts at the cross-roads between ROS and Wnt/β-catenin to regulate indirectly bone metabolism.