The supply of oxygen to the myocardium is determined by coronary blood flow and oxygen carrying capacity. Coronary blood flow is a dynamic process modulated via multiple parameters. Cardiac metabolism is also affected by several factors. Under normal physiologic conditions, the demand is easily met by the supply of oxygen. In fact, there is a significant reserve on the supply side. Under certain pathologic states such as coronary artery disease, the supply of oxygen may be exhausted and an imbalance between supply and demand occurs which is translated into ischemia. The area of myocardium most susceptible to ischemia is the subendocardium due to mechanical and metabolic forces. In therapy of coronary artery disease, attention should be directed to directional changes in factors influencing supply and demand to improve blood flow to the most susceptible area.