Traditionally, invasive coronary physiological assessment has focused on the epicardial coronary artery. More recently, appreciation of the importance of the coronary microvasculature in determining patient outcomes has grown. Several invasive modalities for interrogating microvascular function have been proposed. Angiographic techniques have been limited by their qualitative and subjective nature. Doppler wire-derived coronary flow reserve has been applied in research studies, but its clinical role has been limited by its lack of reproducibility, its lack of a clear normal value, and the fact that it is not specific for the microvasculature but interrogates the entire coronary circulation. The index of microcirculatory resistance—a thermodilution-derived measure of the minimum achievable microvascular resistance—is relatively easy to measure, more reproducible, has a clearer normal value, and is independent of epicardial coronary artery stenosis. The index of microcirculatory resistance has been shown to have prognostic value in patients with ST-segment–elevation myocardial infarction and cardiac allograft vasculopathy after heart transplantation. Emerging data demonstrate its role in evaluating patients with chest pain and nonobstructive coronary artery disease. Increasingly, the index of microcirculatory resistance is used as a reference standard for invasively assessing the microvasculature in clinical trials.