Abstract Forkhead box transcription factor , class0 (FOXO) is a mammalian homologue ofDAF-I6, which is known to regulate the lifespan of Caenorhabditis elegansand includes subfamilies offorkhead transcription factors such asFOXO1 (FKHR), FOX03 (FKHRLI),FOX04 (AFX) and FOX06. All these FOXO members are expressed in the brain with different spatial patterns. FOXOI is phosphorylated on three sites (Thr-24, Ser-256 and Ser-3I9) in phosphatidylinositol 3-kinase (PI3-K)/Akr-dependent manner, thereby inhibiting apoptosis signals. We here documented dephosphorylation of FOXO1, FOX03 and FOX04 following transient forebr ain ischemia with its concomitant translocation into the nucleus in neurons in the gerbil and mouse brains. The dephosphorylation ofFOXO1 following brain ischemia is in part mediated by constitutively active calcineurin in the mouse hippocampus. The activation ofFOXOs preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury.The FOXO1activation isaccompanied by an increase in DNAbindingactivity for FOXOl -responsive element on the Fas ligand promoter. Thus, downstream targets induced by FOXO1 include Fas ligand and Bcl-2-interacting mediator of cell death (Bim) in the brain ischemia. Accumulating evidence documented how FOXO activation is involved in the mechanisms of ischemic cell death. In this chapter, we document the activation mechanism ofFOXO factors following brain ischemia and define their downstream targets underlying neuronal death. The pathophysiological relevance ofcrosstalk between FOXOs and calcineurin pathways is also discussed. Finally, we propose therapeutic perspectives to rescue neurons from delayed neuronal death by promoting the Akt signaling. Vanadium compounds, protein tyrosine phosphatase inhibitor, up-regulates Akt activity in the brain and thereby rescues neurons from delayed neuronal death by inhibiting FOXO-dependent and -independent death signals in neurons.