Insulin-like growth factor-I (IGF-I) has significant structural homology with proinsulin. IGF-I binds to insulin receptors, stimulates insulin-like actions and enhances insulin sensitivity. However, because circulating IGF-I is bound to high-affinity binding proteins and has relatively low affinity for insulin receptors, most of its ability to alter insulin sensitivity is mediated indirectly (i.e. through suppression of growth hormone, a known insulin antagonist). Direct effects of IGF-I on insulin actions are tissue specific, occurring principally in skeletal muscle and kidney. Genetic manipulations in experimental mouse models have been used to analyze the role of endogenous IGF-I on insulin action. These studies have shown that suppression of growth hormone is important for enhancing insulin action in the liver and that deletion of the IGF-I receptor in skeletal muscle results in severe insulin resistance. IGF-I also suppresses renal gluconeogenesis, which might contribute to its glucose-lowering actions. In humans, IGF-I enhances insulin sensitivity and lowers blood glucose in patients with either extreme insulin resistance or type 2 diabetes. It also decreases insulin requirement in patients with insulin-deficient diabetes. Taken together, these findings suggest that IGF-I is functioning coordinately with insulin to regulate glucose homeostasis.