Modern coronary diagnostic methods, including cardiac computed tomography and intracoronary imaging, allow the identification of vulnerable coronary plaques with a high probability of complicating and causing acute coronary syndrome. The treatment limited to the plaques responsible for ischemic events could not be enough to prevent major cardiovascular events because most flow-limiting plaques are quiescent or slowly evolving. In several cases the plaques responsible for acute event determine a moderate reduction of the vessel lumen but have well-defined characteristics of vulnerability. The purpose of this review is (i) to describe the characteristics of these plaques based on both the pathological anatomy and computed tomography and intracoronary imaging findings and the associated clinical risk of developing future coronary events; (ii) to evaluate available trials on early treatment of vulnerable plaques by percutaneous revascularization; and (iii) to propose a decision-making algorithm in primary prevention integrating the search for myocardial ischemia and vulnerable plaques.