Coronary artery disease (CAD) is one of the major causes of death in Japan. Fractional flow reserve with angiography is a well validated method for identifying significant focal stenosis, but is not applied for the estimation of hyperemic vasodilatory capacity in the myocardium. Coronary flow reserve (CFR) estimated from sequential myocardial perfusion images obtained by blood flow tracers and positron emission tomography (PET) is a quantitative value. CFR is regulated not only by focal stenoses but also by diffuse atherosclerosis and coronary microvascular dysfunction (CMD) in patients with CAD. Accordingly, low CFR is shown to be a strong predictor of cardiac death in combination with anatomical disease burden. Optimal medical therapies such as beta-blockers, angiotensin converting enzyme (ACE) inhibitors, statins, and medications for diabetes could increase CFR by improving CMD at the early stage of CAD. It is also important to clarify the effects of coronary revascularization for focal stenoses on CFR. This paper focuses on the application of CFR estimated by cardiac PET to the evaluation of per-patient atherosclerotic burden and microvascular dysfunction.