Blood platelets (PLTs) play a key role in atherothrombosis due to their ability of thrombus formation after rupture of an atherosclerotic plaque. Numerous clinical trials have established the efficacy of PLT function blockade in the prevention of acute coronary syndromes. Meanwhile, nearly all patients undergoing cardiopulmonary bypass grafting present with anti-PLT therapy. PLTs interact also with endothelial cells, leukocytes, and smooth muscle cells and are involved in vascular inflammation. This may result in an excessive fibroproliferative response after vessel dilatation. Furthermore, many PLT blockers are associated with response variability up to nonresponsiveness leading to increased reintervention and transfusion rates both identified as independent risk factors for an adverse clinical outcome after coronary interventions. Summarizing the role of PLTs for normal hemostasis and the pathophysiology of atherothrombosis, this review describes the current status of anti-PLT therapy and highlights some new anti-PLT drugs in the prevention of serious cardiovascular events.