Forkhead box O (FoxO) transcription factors play important roles in cellular physiology and biology. Recent findings indicate that FoxOs are also involved in the development of major depressive disorder. Alterations in the upstream molecules of FoxOs, such as brain derived neurotrophic factor or protein kinase B, have been linked to depression. Antidepressants, such as imipramine and venlafaxine, modify the FoxOs phosphorylation. Furthermore, FoxOs could be regulated by serotonin and norepinephrine receptor signaling as well as the hypothalamic pituitary adrenal axis, all of which are involved in the pathogenesis of depression. FoxOs also regulate neuronal morphology, synaptogenesis and adult hippocampal neurogenesis, which are viewed as candidate mechanisms for the etiology of depression. In this review, we emphasize the possible roles of FoxOs during thedevelopment of depression and make some strategic recommendations for future research. We propose that FoxOs and its signaling pathways may constitute potential therapeutic targets in thetreatment of depression. (C) 2015 Elsevier Ltd. All rights reserved.