The hallmark of ischemic heart disease is the presence of focal obstructions in the major coronary arteries. Classically, epicardial stenoses are thought to exert their pathogenetic role mainly through a limitation on maximal flow capacity in the distal vascular bed. Ischemia is thus thought to occur whenever oxygen consumption exceeds the flow availability. Although a number of experimental studies confirmed these assumptions, the adherence of this experimental model with the clinical observations is still far from being convincing. Evidence now exists that atherosclerosis causes more profound alterations in the regulation of myocardial perfusion, besides the hydraulic effects of epicardial obstructions. These alterations affect endothelial regulation of coronary vasomotor tone both in the large arteries and in the distal microcirculation. In agreement with this experimental evidence, an abnormal response to endothelium-mediated vasodilators has been reported in patients with coronary artery disease. Moreover, several studies also reported an abnormal response of atherosclerotic coronary microcirculation to atrial pacing tachycardia and dipyridamole, which are thought to be largely endothelium independent. An even more striking observation is the finding of an intense microvascular constrictor response in the myocardium, supplied by a severely stenotic coronary artery, to pacing-induced ischemia. This observation strongly suggests that coronary microcirculation might aggravate the flow reduction imposed by the epicardial stenosis, thus playing some role in the pathogenesis of ischemia. This phenomenon might reflect the presence of a primary abnormality of coronary microcirculation in patients with coronary artery disease or the existence of a pressure-oriented regulation of vascular tone which prevent trans-stenotic pressure drop by means of a heterogeneously distributed microcirculatory vasoconstriction.