The in vivo actions of growth hormone (GH) on insulin activity and glucose homeostasis were examined in the GH-deficient Little mouse. The insulin-like action of GH was revealed during glucose tolerance tests on the animals after acute treatment with the hormone and the insulin-antagonistic action was demonstrated in both glucose tolerance tests and insulin tolerance tests on the mice after chronic GH infusion. The primary mechanism of the GH actions is to influence the responses of the target tissues to circulating insulin in vivo. The pancreatic function seems to be of little importance in the alteration of glucose metabolism after acute exposure to GH as no significant change of the levels of plasma insulin was detected. It is concluded that the GH-deficient Little mouse is an ideal laboratory model for the elucidation of the molecular mechanism of the interaction between insulin and GH in the regulation of carbohydrate metabolism.