The muscle microcirculation regulates delivery of nutrients and oxygen to myocytes, acutely and chronically matching supply and demand. Consequently, microvascular characteristics such as resistance, surface area and flow regulate myocellular glucose uptake(1) and exercise tolerance. Microvascular endothelium plays a critical role in these functions through control over vascular resistance, angio- and arteriogenesis, distribution of blood flow and inflammation. In man, insulin-stimulated perfusion of capillaries in muscle is closely related to insulin-stimulated glucose uptake(1;2). In rodent models, insulin-induced NO synthesis has been shown to regulate glucose uptake through transendothelial transport (TET) of insulin from blood to the muscle interstitium. The balance between secretion of NO and endothelin-1 by endothelial cells is an important mediator of these effects. Insulin’s effects on muscle perfusion are impaired in obesity and are regulated by bioactive products of adipose tissue, adipokines(3). Adipokines such as adiponectin, fatty acids and cytokines, activate distinct signaling mediators in vascular endothelium, including 5’AMP-activated protein kinase, protein kinase C theta (PKCθ) and c-jun N-terminal kinase, respectively.It has been recently established that perivascular adipose tissue (PVAT), found around arteries, veins and the proximal part of microvascular beds (4), is a functionally relevant source of adipokines. In the aorta and coronary circulation, PVAT is a site of inflammation in atherosclerosis (5). In resistance arteries, PVAT determines vascular tone through direct actions on smooth muscle (6), and through indirect effects on insulin signaling in vascular endothelium (7). These effects of PVAT are effectuated by 5’AMP activated protein kinase (AMPK) and inflammatory signaling through c-jun N-terminal protein kinase (JNK). Infiltration of inflammatory cells and the resultant signaling cascades play critical roles in impairment of vasodilator effects of PVAT in obesity(6,7). A mediating role of PVAT in the relationship between obesity and insulin resistance in man is further supported by our recent finding that vasodilator effects of muscle PVAT are impaired in obese subjects.In conclusion, recent clarification of the complex relationships between local adipose tissue, microvascular endothelium and muscle cells provides new avenues for prevention of type 2 diabetes and cardiovascular disease in the near future.