The current treatment of ischemic heart disease does not provide consistent control of anginal symptoms and does not assure effective protection from main adverse coronary events (MACE), including cardiac death and myocardial infarction. Most prescribed drugs, including ß-blockers, calcium channel blockers, and nitrates, are directed toward restoration of the coronary supply-to-demand ratio, which is regarded as the main pathogenetic mechanism of myocardial ischemia. Innovative approaches, focused on the protection of coronary microcirculation from ischemia-reperfusion damage in acute coronary syndromes and on shifting cardiac energy metabolism from fatty acid to glucose, have been shown to improve symptoms and preserve left ventricular function. Given their different mechanism of action, these new strategies offer the opportunity of combination with conventional agents, with greater benefit and improved patient tolerance...