This review describes efforts to use near-infrared (NIR) spectroscopy to identify chemical components of coronary artery plaques as a means to assess vulnerability. Near-infrared spectroscopy has been well-validated by the physical sciences as a method to characterize chemical composition of various bio-materials and could be ideal to detect vulnerable coronary plaques in patients. Recent studies in aortic and coronary artery autopsy specimens have confirmed the ability of the technique to identify lipid-rich thin-cap fibroatheromas through blood. A catheter-based system has been developed to address the challenges-of access to the coronary artery, blood, motion, and the need to scan-that must be overcome for use in patients. Initial clinical experience in six patients with stable angina demonstrates that high-quality NIR spectra can be safely obtained. Additional studies are planned to validate the ability of the technique to identify lipid-rich coronary artery plaques and ultimately link chemical characterization with subsequent occurrence of an acute coronary syndrome.