Background: Experimental data in human subjects demonstrate that growth hormone (GH) acutely inhibits glucose disposal in skeletal muscle. The insulin-antagonistic effects are clinically relevant since active acromegaly is accompanied by glucose intolerance, whereas children with GH deficiency may develop fasting hypoglycemia. At the same time, GH stimulates the turnover and oxidation of free fatty acids (FFAs), and there is experimental evidence to suggest a causal link between elevated FFA levels and insulin resistance in skeletal muscle. During fasting, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation, which seems to constitute a favorable metabolic adaptation. Conclusions: Observational data in GH-deficient adults do not indicate that GH replacement is associated with significant impairment of glucose tolerance; however, care should be taken to avoid overdosing and to monitor glycemic control.