There is an imperative need to distinguish stable from unstable and vulnerable plaques because of the occurrence of thrombosis following rupture of the plaque. Imaging techniques, invasive and noninvasive, are used routinely for the assessment of visualization and quantification of this pathology, even if invasive techniques cannot be applied in the screening of atherosclerotic plaques and noninvasive imaging has low reproducibility. The aim of this review was to verify the suitability and the advantages of using vibrational spectroscopy in the study of human atherosclerotic plaques. The utilization of validated vibrational techniques in clinical trials may be of great importance for the ability to diagnose the early onset of a disease, rapidly, noninvasively and unambiguously. These techniques, by using a worldwide accepted protocol in spectral investigation of bioclinical changes in the human body, have been successfully applied to assess vulnerable plaques in ex vivo and in vivo models, constituting a potentially useful support to classical clinical imaging techniques. It is conceivable that this fingerprinting approach, with further clinical validation, is ready to be developed for use and at the disposal of commercial and easy-to-use spectrometers, equipped with catheter-based systems for the in vivo imaging of atherosclerosis plaques.