In the recent years it has become apparent that angiography-based assessment of coronary artery stenosis suffers from considerable inaccuracy and pitfalls. Besides interobserver variability in assessing stenosis severity, the correlation between angiographic severity and ischemia is suboptimal. Percutaneous coronary intervention (PCI) guided by the physiologic lesion assessment employing fractional flow reserve (FFR) is rendered superior to angiographic lesion assessment and proven to improve cardiovascular outcomes and reduce cost. In this manuscript we discuss the accepted and emerging clinical indications for FFR use. The correlation between FFR and symptoms, stress imaging and intravascular ultrasound are reviewed along with the inherent limitations and pitfalls of these diagnostic technologies. The data regarding the correlation between Instantaneous (vasodilator free) wave-free ratio (iFR) and conventional FFR is summarized.