Treatment strategies for patients with coronary artery disease (CAD) should be based on objective evidence of inducible ischemia in the subtended myocardium to improve clinical outcomes, symptoms, and cost-effectiveness. Fractional flow reserve (FFR) is the most verified index to-date for invasively evaluating lesion-specific myocardial ischemia. Favorable results from large clinical trials that applied FFR-guided percutaneous coronary intervention (PCI) prompted changes in coronary revascularization guidelines to emphasize the importance of this ischemia-based strategy using invasive coronary physiology. However, the frequency of functional evaluations is lacking in daily practice, and visual assessment still dominates treatment decisions in CAD patients. Despite recent efforts to integrate functional and anatomical assessments for coronary stenosis, there is considerable discordance between the 2 modalities, and the diagnostic accuracy of simple parameters obtained from current imaging tools is not satisfactory to determine functional significance. Although evidence that supports or justifies anatomy-guided PCI is more limited, and FFR-guided PCI is currently recommended, it is important to be aware of conditions and factors that influence FFR for accurate interpretation and application. In this article, we review the limitations of the current anatomy-derived evaluation of the functional significance of coronary stenosis, detail considerations for the clinical utility of FFR, and discuss the importance of an integrated physiologic approach to determine treatment strategies for CAD patients.