Coronary anatomy and myocardial blood flow are major determinants of clinical symptomatology and survival in patients with coronary artery disease. While coronary anatomy has been successfully assessed by coronary angiography and intravascular ultrasound imaging, measurements of coronary blood flow are more difficult and their prognostic value has not been definitively evaluated. Measurements of coronary flow reserve (CFR), defined as maximal hyperemic flow divided by resting flow, have been used to assess the functional significance of coronary artery lesions. However, functional assessment of epicardial coronary lesions is limited by several factors, such as diffuse coronary artery disease, small-vessel disease, regional variations in myocardial flow, endothelial dysfunction, and left ventricular hypertrophy. CFR can be measured by several techniques, each one with distinct advantages and limitations, which are discussed in this review. An important distinction is between techniques that measure coronary blood flow (e.g., positron emission tomography) and those that measure blood flow velocity (e.g., Doppler catheters), from which coronary velocity reserve (CVR) is calculated. Although clinical CFR measurements have been possible for over fifteen years, their implementation in patient care has been slow due to several factors including the requirement for a sophisticated technology, the difficult interpretation of CFR results, and the limited knowledge of their prognostic value. While a normal CFR in patients with single vessel coronary disease is associated with a good prognosis, the converse has not been established, i.e., that there is a critical reduction in CFR that requires interventional treatment. A recent study (DEBATE) showed a decrease in the incidence of cardiac events at 6 months after coronary balloon angioplasty in patients with a post-procedural percent diameter stenosis < 35% and a CVR > 2.5. The complex relation between coronary anatomy, myocardial perfusion, and patient outcome have enormous implications for both patient care and health costs, which need to be addressed in future prospective trials.