Diagnostic techniques to identify vulnerable plaques are rapidly evolving. Intravascular ultrasound (IVUS) has the ability to detect and localize plaque as well as quantitate plaque burden. Recent IVUS studies have suggested that patients presenting with acute coronary syndromes have an approximate 25% incidence of additional ruptured plaques in arteries other than the culprit lesion. The ability of IVUS to detect vulnerable plaques before rupture is currently being evaluated by novel techniques. Initially, IVUS was shown to be able to characterize plaque broadly as calcified or fibrofatty but was limited in its ability to more precisely detect lipid-rich plaques, necrotic cores, and thrombus. Recent advances in new applications of IVUS, such as integrated backscatter, wavelet analysis, and virtual histology, have focused on evaluating and mathematically transforming the radiofrequency signal from ultrasound waves into a color-coded representation of plaque characteristics such as lipid, fibrous tissue, calcification, and necrotic core. In addition, targeted contrast agents, applicable to both intravascular and transthoracic studies, are being evaluated in experimental models and aim to highlight specific plaque components, such as endothelial adhesion molecules and other plaque components that might be useful in targeting vulnerable plaques. These advances pave the way for future clinical trials in assessing the ability of such techniques to diagnose vulnerable plaques and to assess the effects of both pharmacologic and mechanical therapies on plaque characteristics.