Acute coronary syndromes (ACS) are the end manifestations of atherosclerosis resulting in angina (chest pain), myocardial ischemia (MI, heart attack), fatal MI (sudden death) or stroke. The underlying cause of ACS is the formation of unstable (vulnerable) atherosclerotic plaque, its rupture and resulting thrombosis. Cardiovascular events are not necessarily caused by large plaques that obliterate the artery. They are caused often by unstable (small or large) plaques that are susceptible to thrombosis and resulting in occlusion. Unlike atherogenesis where endothelial cells, smooth muscle cells and macrophages all play a role, localized macrophage activity alone may determine plaque stability and drive plaque rapture. Therapies to modulate macrophage lipid content and inflammatory state are currently unavailable. Cholesterol dependent and cholesterol independent pathways, both contribute to macrophage inflammation and apoptosis. New targeted therapies are emerging based on exciting research and drugs that work through these targets may have a greater impact in reducing the cardiovascular risk beyond that achieved thus far by statins, antithrombotics and other risk reducing therapies that are currently on the market.