Since its anatomic discovery in the 19th century, the endothelium was considered to fulfill no other purpose than that of a physical barrier between blood and tissue, until Furchgott and colleagues defined endothelium-dependent vasoreactivity in the late 1970s. Henceforth, a functional paradigm defined the balance between endothelium-derived relaxing factors and endothelium-derived contracting factors as the hallmark of endothelial cell integrity. As a consequence, any reflection of a deviation from this state was defined as endothelial dysfunction, most notably the impairment of vasorelaxation in response to pharmacologic stimuli such as acetylcholine or nonpharmacologic stimuli such as shear stress and cold pressor. Within the coronary artery tree these alterations have been recognized before the development of obstructive coronary artery disease, affecting the microcirculation before the epicardial conduit vessel. Furthermore, recent clinical trials outlined the prognostic significance of these changes, whereby impairment of increase in coronary blood flow in response to endothelium-dependent stimuli seemed to be of utmost importance. Thus it is intriguing to speculate on the evolving role of myocardial perfusion imaging in combination with pharmacologic and nonpharmacologic stimuli for the noninvasive assessment of coronary endothelial dysfunction in patients at risk for future adverse events. At a minimum, this review aims to put endothelial dysfunction into an imaging perspective beyond the scope of the conventional approach.