Advances in coronary imaging are needed to enable the early detection of plaque segments considered to be 'vulnerable' for causing clinical events. Pathological studies have contributed to our current understanding of these vulnerable or unstable segments of plaque. Intravascular ultrasonography (IVUS) has provided insights into the morphology of atherosclerosis, the mediators of plaque progression and the factors associated with acute coronary syndrome (ACS). In addition, the demonstration of pancoronary arterial instability has highlighted that ACS involves a multifocal disease process. Various second-generation intravascular imaging technologies-employing advanced processing of ultrasound radiofrequency backscatter signals, light-based imaging, spectroscopic imaging and molecular targeting-possess inherent advantages for the identification of meaningful surrogates of plaque instability. The fusion of these imaging technologies within a single imaging catheter is likely to allow for greater synergism in image quality and early disease detection. However, natural-history studies to validate the use of these novel imaging tools for enhanced risk prediction are needed before these strategies can be incorporated into mainstream clinical practice.