Myocardial ischemia is recognized as an important mechanism increasing the risk for cardiovascular events in both symptomatic and asymptomatic patients. In addition to obstructive coronary diseases, systemic inflammation, macro- and microvascular function are additional important mechanisms contributing to the ischemic myocardium. Accumulating evidence indicates that coronary flow reserve (CFR) is a quantitative measurement of ischemia including integrated information on structure and function of the coronary artery at all levels. Not surprisingly, CFR has been shown to confer strong prognostic value for hard cardiovascular (CV) events in a number of relevant patient cohorts. Using high-resolution imaging, it is now possible to study coronary arteries from mouse to man. Therefore, CFR may be an important translational tool to risk-stratify patients and to perform both preclinical and clinical proof-of-concept studies before investing in large-scale outcome trials, thus improving the translational value for novel CV targets.