Myocardial ischemia is a leading cause of death worldwide, and it corresponds to the imbalance between blood supply and myocardial demand. Epicardial coronary artery disease (CAD) is detected on the basis of coronary angiogram, whereas invasive detection of myocardial ischemia induced by coronary stenosis is commonly based on fractional flow reserve (FFR). The use of FFR for revascularization decision-making demonstrated clinical benefit and cost-effectiveness compared with that of angiographic indices. Discrepancies between anatomical metrics and physiological assessment of CAD are frequent, which lead to change in revascularization decision from angiography compared to functional evaluation of CAD. Despite several clinical studies and guidelines recommending with high level of evidence demonstrating that FFR should be adopted in stable CAD, revascularization decision-making is still based on coronary angiogram in current practice. Because of the unique coronary anatomy, coronary stenosis characteristics, risk factors profile, and microcirculation quality, the unique evaluation based on epicardial coronary stenosis threshold failed to be a landmark of ischemia compared with FFR. Furthermore, coronary angiogram can detect only epicardial vessels, which represent only 10% of the entire coronary vasculature; therefore, microcirculation is not seen and is poorly assessed in clinical practice. Thus, the role of microcirculation is of importance in myocardial ischemia and might impact these discrepancies between angiography and FFR evaluation of CAD. In this review, we aimed to describe the poor correlation between anatomical evaluation compared with physiological evaluation to detect myocardial ischemia induced by coronary stenosis as well as the clinical implications of this visual–functional mismatch.