Sudden death or acute coronary syndromes are frequently the first manifestation of plaque rupture at non-culprit lesions. Thus, identification of high-risk non-culprit plaques may have significant impact on the prognosis of patients with coronary artery disease. At present a widely accepted diagnostic method to prospectively identify such 'high-risk' plaques is not available. Improved identification of high-risk plaques by novel imaging coronary modalities currently available is a goal of great importance since it will result in major decreases in coronary artery disease morbidity and mortality. Potential new treatments with systemic, regional, and local approaches have been proposed. In this review article we focus on common and different morphologic characteristics between culprit and non-culprit lesions, the natural history of non-culprit lesions, and potential methods to identify the high-risk lesions for future adverse cardiovascular events.