Forkhead box O (FOXO) transcription factors play an important role in modulating metabolic functions. FOXO is regulated by several modifications, but one of the most critical is phosphorylation and nuclear exclusion by Akt. Given the impact of insulin signaling on Akt-mediated phosphorylation of FOXO and the relatively high expression of Foxo1 in insulin-responsive tissues, this transcription factor is highly poised to regulate energy metabolism. When nutrient and insulin levels are low, Foxo1 promotes expression of gluconeogenic enzymes. Conversely, in the fed state, insulin levels rise and stimulate uptake of glucose primarily into skeletal muscle and other organs, including adipose tissue. Under certain pathophysiologic conditions, including insulin resistance, negative signaling to Foxo1 is compromised. Further clarification of the role of Foxo1 in insulinresponsive tissues will strengthen our understanding and allow us to better combat insulin resistance and diabetes mellitus.