The quantitative assessment of coronary flow reserve (CFR) may be useful for the functional evaluation of coronary artery disease (CAD), allowing judgment of its severity, tracking of disease progression, and evaluation of the anti-ischemic efficacy of therapeutic strategies. Invasive techniques, such as intracoronary Doppler ultrasound and the pressurederived method, which directly assess CFR velocity and fractional flow reserve, have been used for the evaluation of the physiologic significance of coronary lesions. Considerable progress has been made in the improvement of technologies directed toward the noninvasive quantification of myocardial blood flow and CFR. Positron emission tomography has emerged as an accurate technique to quantify CFR. The absolute measurements obtained with this noninvasive approach have been widely validated. Nevertheless, it has not been applied to routine studies because of its high cost and complexity. On the other hand, technetium 99m-labeled tracers have been largely used for the evaluation of myocardial perfusion with single photon emission computed tomography (SPECT) imaging in patients with suspected or known CAD. Recently, attempts to estimate CFR with SPECT tracers have been made to obtain, with noninvasive methods, data for quantitative functional assessment of CAD. This review analyzes the relative merit and limitations of CFR measurements by cardiac SPECT imaging with Tc-99m-labeled tracers and describes the potential clinical applications of this technique. (