The endothelium exerts a paracrine function by releasing a number of mediators that control vascular tone and smooth muscle cell proliferation, platelet aggregation, monocyte and leukocyte adhesion, and thrombosis. Coronary microvascular endothelium is involved not only in the control of blood flow to myocardial tissue, but also in the regulation of myocyte metabolism and contractile function. Thus, coronary microcirculation might be the initial site of pathological events leading to development and progression of cardiac dysfunction and failure. Although this pathophysiological mechanism has been hypothesized on the basis of very solid clinical and experimental evidence, yet it has not been sufficiently considered and explored by the scientific community. The present review highlights the studies that have principally contributed to define the critical role played by coronary microvascular endothelium in the regulation of cardiac function, and to elaborate the intriguing hypothesis that coronary microcirculatory dysfunction is a major pathogenetic factor involved in the genesis of heart failure.