Assessment of the coronary microvasculature in the clinical setting is a key issue, given that microvascular dysfunction itself has a predictive value for cardiovascular events. The index of microcirculatory resistance (IMR) is an invasive method of interrogating the microvasculature and provides further insight into the physiology of cardiovascular diseases. It is simple and readily applicable in the cardiac catheterization laboratory where many patients first present for evaluation of their coronary circulation. In contrast to other invasive and non-invasive tests, this method is known to be stable and reproducible under various hemodynamics and even in the presence of epicardial coronary artery stenosis. IMR has been shown to have prognostic value in patients with ST-segment elevation myocardial infarction; therefore it can be a surrogate marker of cardiovascular events. At the same time, it has the potential to be a therapeutic as well as an investigational tool in the physiology of cardiovascular diseases. This review summarizes the development of IMR, tips and tricks for its measurement, and its usefulness in various clinical settings.