There are many mechanisms that contribute to the regulation of coronary blood flow including vasodilatory metabolites, myogenic regulation, flow- or shear stress-mediated vasodilation, and neurohumoral influences. It is interesting to note that coronary arterioles of varying sizes appear to possess different sensitivities to these regulatory factors, but each appears to dominate the control of a particular segment of the microvasculature. For example, during metabolic hyperemia the smallest arterioles seem to be most sensitive to the effects of metabolites, but metabolic and myogenic mechanisms that dictate the tone of upstream microvessels likely act in concert to facilitate the overall adjustments in coronary vasomotor tone. Neurohumoral mechanisms, seem to modulate the robustness of these intrinisic adjustments, perhaps by restraining the extent of vasodilation. The purpose of this review is to discuss these many regulatory mechanisms and also present a framework by which the vasoactive reactions elicited by these different mechanisms are integrated into coordinated responses of the entire coronary vascular network.