Forkhead transcription factors of the FoxO fam ily have important roles in cellular proliferation, apoptosis, differentiation and stress resistance. FoxO proteins also play important roles in metabolism of complex organisms. FoxOl regulates glucose and lipid metabolism in liver, as well as preadipocyte, myoblast and vascular endothelial cell differentiation. In the hypothalamus, FoxO controls food intake. In this chapter, we review the role of FoxO in pancreatic β cells. Pancreatic β cells secrete insulin to maintain the plasma glucose levels in a strict physiological range. Defects of β-cell function cause diabe tes. The expression pattern of FoxOl during pancreatic organogenesis is similar to that of Pdxl, Nkx2.2 and Pax4, transcription factors known to be critical for β-cell development. FoxOl is expressed in a subset of pancreatic duct cells, in which insulin and/or Pdxl are occasionally expressed. FoxOl inhibits β-cell proliferation through suppression of Pdxl by competing with FoxA2 and protects against β-cell failure induced by oxidative stress through NeuroD and MafA induction. Thus, a series of FoxOl studies in pancreas suggested that FoxO 1 plays important roles in pancreatic β-cell differentiation, neogenesis, proliferation and stress resistance. Genetic or pharmacological manipulation of FoxO can be used to prevent β-cell failure or aid in the differentiation of uncommitted endocrine progenitors into β cells for transplantation.