Skeletal muscle is the major constituent of lean body mass and a major determinant of energy expenditure both at rest and during physical activity. Growth hormone, in turn, influences muscle mass as well as energy expenditure. Growth hormone substitution in adults increases muscle mass by 5-10%, but part of the effect is attributed to rehydration rather than protein accretion. In addition, GH regulates substrate metabolism in muscle and in particular antagonizes insulin-stimulated glucose disposal. This effect is linked to increased free fatty acid (FFA) flux but the molecular mechanisms remain unclear. During fasting, GH-induced insulin resistance may be favorable by reducing the demand of gluconeogenesis from protein. But in the postprandial phase, GH exposure may compromise glucose tolerance via the same mechanisms. Understanding the mechanisms whereby GH antagonizes insulin-stimulated glucose disposal in muscle is an important future research field with implications for a variety of clinical conditions ranging from malnutrition to obesity and type 2 diabetes.