Angiography is notoriously poor at distinguishing ischemia-producing from non–ischemiaproducing intermediate coronary lesions. Here, three invasive modalities for evaluating the physiologic significance of moderate coronary stenoses are reviewed: Doppler wire–derived measurement of coronary flow reserve (CFR), coronary pressure wire–derived fractional flow reserve (FFR), and intravascular ultrasound (IVUS) imaging. Studies investigating the correlation between each of these modalities and various noninvasive tests (eg, nuclear perfusion imaging or stress echocardiography) are discussed. Each of these invasive modalities has its limitations: CFR is limited by its dependence on heart rate and blood pressure, calling into question its reproducibility; both FFR and CFR are limited by their reliance upon achieving maximal hyperemia; and IVUS is limited by the fact that it provides anatomic information only. Ultimately, FFR appears to be the ideal method for interrogating intermediate coronary lesions.