Experimental models of atherogenesis have provided a growing body of information about molecular mechanisms of plaque growth; however, transition from coronary stability to instability is less well understood due to the lack of animal models reflective of human disease. The abrupt clinical presentation of acute coronary syndromes gives a strong signal of discontinuity in the natural history of atherothrombosis. The causes of such discontinuity are complex, probably multiple, and still largely unknown. A better knowledge of the causes of coronary instability might allow identification of new therapeutic targets aimed at the preservation of plaque stability in those subjects in whom primary prevention fails to prevent plaque growth. The goal of this review was to propose a pathogenetic classification of acute coronary syndromes that might help in the search of new diagnostic algorithms and therapeutic targets.