Physiological and pathophysiological roles of K_ATP channels have been clarified recently in genetically engineered mice. The Kir6.2-containing K_ATP channels in pancreatic ß-cells and the hypothalamus are essential in the regulation of glucose-induced insulin secretion and hypoglycemia-induced glucagon secretion, respectively, and are involved in glucose uptake in skeletal muscles, thus playing a key role in the maintenance of glucose homeostasis. Disruption of Kir6.1-containing K_ATP channels in mice leads to spontaneous vascular spasm mimicking vasospastic (Prinzmetal) angina in humans, indicating that the Kir6.1-containing K_ATP channels in vascular smooth muscles participate in the regulation of vascular tonus, especially in coronary arteries. Together with protective roles of K_ATP channels against cardiac ischemia and hypoxia-induced seizure propagation, it is now clear that K_ATP channels, as metabolic sensors, are critical in the maintenance of homeostasis against acute metabolic changes.