The secretions of the pancreas drain into the portal vein just upstream of the liver. This anatomical arrangement is an important component of hepatic function since the pancreatic hormones are key regulators of intermediary metabolism in the liver. In response to moderate-intensity exercise, the secretion of glucagon and insulin from the pancreas generally increase and decrease, respectively. This element of the endocrine response to exercise is critical to the maintenance of glucose homeostasis during exercise. The rise in glucagon and fall in insulin are important for the stimulation of hepatic glycogenolysis. The glucagon response is essential for the exercise-induced increase in gluconeogenesis. In addition, glucagon and insulin are also important to the increase in hepatic fat oxidation during exercise. The fall in insulin enhances the mobilization of NEFA's from adipose tissue and as a result the availability of NEFA's to the liver. The increase in glucagon enhances the oxidation of these NEFA's by stimulating pathways for fat oxidation inside the liver. Hepatic fractional amino acid extraction is increased by glucagon action during exercise. Moreover, the increase in glucagon facilitates the channeling of amino acid carbons to glucose and may play a role in disposal of associated nitrogen. Because of the important roles that glucagon and insulin play, any physiological or pathological condition that affects their secretion or efficacy will impact on the metabolic response to exercise.