Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. Glucose homeostasis is achieved by adjusting endogenous glucose production as well as glucose uptake by peripheral tissues in response to insulin. In the fasted state, the liver is primarily responsible for maintaining glucose levels, with FoxO1 playing a key role in promoting the expression of gluconeogenic enzymes. Following feeding, pancreatic beta cells secrete insulin, which promotes the uptake of glucose by peripheral tissues including skeletal muscle and adipose tissue, and can in part suppress gluconeogenic enzyme expression in the liver. In addition to directly regulating metabolism, FoxO1 also plays a role in the formation of both adipose tissue and skeletal muscle, two major organs that are critical for maintaining energy homeostasis. The importance of FoxO1 in energy homeostasis is particularly striking under conditions of metabolic dysfunction or insulin resistance. In obese or diabetic states, FoxO1-dependent gene expression promotes some of the deleterious characteristics associated with these conditions, including hyperglycemia and glucose intolerance. In addition, the increase in pancreatic beta cell mass that normally occurs in response to a rise in insulin demand is blunted by nuclear FoxO1 expression. However, under these same pathophysiological conditions, FoxO1 expression may help drive the expression of genes involved in combating oxidative stress, thereby preserving cellular function. FoxO1 may also be involved in promoting the switch from carbohydrate to fatty acid as the major energy source during starvation.