In order to sustain viability, it is not possible for nutrients to diffuse from the chambers of the heart through all the layers of cells that make up the heart tissue. Thus, the coronary circulation is responsible for delivering blood to the heart tissue itself (the myocardium). The normal heart functions almost exclusively as an aerobic organ with little capacity for anaerobic metabolism to produce energy. Even during resting conditions, 70 to 80% of the oxygen available within the blood circulating through the coronary vessels is extracted by the myocardium. It then follows that because of the limited ability of the heart to increase oxygen availability by further increasing oxygen extraction, increases in myocardial demand for oxygen (e.g., during exercise or stress) must be met by equivalent increases in coronary blood flow. Myocardial ischemia results when the arterial blood supply fails to meet the needs of the heart muscle, for oxygen and/or metabolic substrates. Even mild cardiac ischemia can result in anginal pain, electrical changes (detected on an electrocardiogram) and the cessation of regional cardiac contractile function. Sustained ischemia within a given myocardial region will most likely result in an infarction.

As noted above, as in any microcirculatory bed, the greatest resistance to coronary blood flow occurs in the arterioles. Blood flow through such vessels varies approximately with the fourth power of these vessels' radii; hence, the key regulated variable for the control of coronary blood flow is the degree of constriction or dilatation of coronary arteriolar vascular smooth muscle. As with all systemic vascular beds, the degree of coronary arteriolar smooth muscle tone is normally controlled by multiple independent negative feedback loops. These mechanisms include various neural, hormonal, local non-metabolic and local metabolic regulators. It should be noted that the local metabolic regulators of arteriolar tone are usually the most important for coronary flow regulation; these feedback systems involve oxygen demands of the local cardiac myocytes. In general, at any one point in time, coronary blood flow is determined by integrating all the different controlling feedback loops into a single response (i.e., inducing either arteriolar smooth muscle constriction or dilation). It is also common to consider that some of these feedback loops are in opposition to one another. Interestingly, coronary arteriolar vasodilation from a resting state to one of intense exercise can result in an increase of mean coronary blood flow from approximately 0.5 to 4.0 ml/min/gram.

As with all systemic circulatory vascular beds, the aortic or arterial pressure (perfusion pressure) is vital for driving blood through the coronaries, and thus needs to be considered as another important determinant of coronary flow. More specifically, coronary blood flow varies directly with the pressure across the coronary microcirculation, which can be essentially considered as the aortic pressure, since coronary venous pressure is near zero. However, since the coronary circulation perfuses the heart, some very unique determinants for flow through these capillary beds may also occur; during systole, myocardial extravascular compression causes coronary flow to be near zero, yet it is relatively high during diastole (note that this is the opposite of all other vascular beds in the body).

Coronary arteries are so vital to the function of heart; whenever disease states are associated with flow restriction through the coronary arteries, and subsequently the remainder of the coronary circulations (capillaries and veins), the effects on cardiac performance are quite dramatic and often fatal. Coronary artery disease (CAD) is generally defined as the gradual narrowing of the lumen of the coronary arteries due to coronary atherosclerosis. Atherosclerosis is a condition that involves thickening of the arterial walls from cholesterol and fat deposits that build up along the endoluminal surface of the arteries. With severe disease, these plaques may become calcified and so large that they produce stenoses within the vessels, and thus permanently increase the vascular resistance which is normally low. When the walls of the coronary arteries thicken, the cross-sectional area of the arterial lumen decreases; resulting in higher resistance to blood flow through the coronary arteries. This steady decrease in cross-sectional area can eventually lead to complete blockage of the artery. As a result, oxygen and nutrient supply to the myocardium drops below the demand of the myocardium. As the disease progresses, the myocardium downstream from the occluded artery becomes ischemic. Eventually, myocardial infarction (or known as a MI) may occur if the coronary artery disease is not detected and treated in a timely manner.

Myocardial ischemia not only impairs the electrical and mechanical function of the heart, but also commonly results in intense, debilitating chest pain known as angina pectoris. However, anginal pain can often be absent in individuals with coronary artery disease when they are resting (or in individuals with early disease stages), but induced during physical exertion or with emotional excitement.