The skeletal muscle is one of the major target organs of insulin and plays an essential role in insulin-induced glucose uptake. Some evidence indicates that insulin delivery to skeletal muscle interstitium through the endothelial cells is the rate-limiting step in insulin-stimulated glucose uptake. Researchers have also found that this process is impaired by insulin resistance in type 2 diabetes and obesity. A recent study of ours demonstrated that insulin signaling in the endothelial cells plays a pivotal role in the regulation of glucose uptake by the skeletal muscle. Specifically, impaired insulin signaling in the endothelial cells, with reduction of insulin-induced eNOS phosphorylation, causes attenuation of the insulin-induced capillary recruitment and insulin delivery, which, in turn reduces glucose uptake by the skeletal muscle in high-fat diet-fed mice. Moreover, restoration of the insulin-induced eNOS phosphorylation in the endothelial cells completely reverses the reduction in the capillary recruitment and insulin delivery, and as a result, significantly restores glucose uptake by the skeletal muscle. In the present review, we describe the recent progress in research on the physiological and pathophysiological roles of endothelial insulin signaling in the regulation of insulin-induced glucose uptake by the skeletal muscle.