For many decades, the severity of coronary artery disease (CAD) and the indication to proceed with either percutaneous coronary intervention (PCI) or surgical revascularization has been based on anatomically derived parameters of vessel stenosis, and typically on the percentage of lumen diameter stenosis (DS%) as determined by invasive coronary angiography (CA). However, it is currently a well-accepted concept that pre-specified thresholds of DS% have a weak correlation with the ischemic and functional potential of an epicardial coronary stenosis. In this regard, the introduction of fractional-flow reserve (FFR) has represented a paradigm-shift in the understanding, diagnosis, and treatment of CAD, but the adoption of FFR into the clinical practice remains surprisingly limited and sub-standard, probably because of the inherent drawbacks of pressure-wire-based technology such as additional costs, prolonged procedural time, invasive instrumentation of the target vessel, and use of vaso-dilatory agents causing side effects for patients. For this reason, new modalities are under development or validation to derive FFR from computational fluid dynamics (CFD) applied to a three-dimensional model (3D) of the target vessel obtained from CA, intravascular imaging, or coronary computed tomography angiography. The purpose of this review was to describe the technical details of these anatomy-derived indices of coronary physiology with a special focus on summarizing their workflow, available evidence, and future perspectives about their application in the clinical practice.