Coronary atherosclerosis is the primary cause of heart diseases in industrialized nations. It has now become clear that coronary atherosclerosis is not simply an inevitable consequence of aging but rather a chronic inflammatory process that can be converted into an acute clinical event by plaque rupture and arterial thrombosis. It is well recognized that platelets play a key role in thrombotic vascular occlusion at the ruptured coronary atherosclerotic plaque, leading to acute ischemic episodes, the acute coronary syndromes (ACSs). In addition, both embolization of platelet aggregates and direct, receptor-mediated platelet adhesion to the postischemic microvascular surface result in obstruction and impairment of coronary microcirculation. Such microvascular disturbance may lead to significant additional tissue injury and aggravate myocardial contractile dysfunction. Novel antiplatelet strategies have contributed substantially to improve the outcome of patients with ACSs. However, the availability of new investigative tools, including genetically modified mouse models of disease, has demonstrated that platelets not only contribute to acute thrombotic vascular occlusion but also participate in the inflammatory and matrix-degrading processes of coronary atherosclerosis itself. Platelet- endothelial cell interactions at lesion-prone sites might trigger an inflammatory response in the vessel wall early in the genesis of atherosclerosis and contribute to destabilization of advanced atherosclerotic lesions. Thus, recent progress in defining the complex multistep process that promotes firm arrest of platelets to the (sub-) endothelium and initiates subsequent platelet activation may lead to the development of new antiplatelet strategies that provide an efficacious prophylactic intervention, in particular, for patients with a high atherosclerotic risk factor profile.