Platelets have a crucial role in haemostasis and atherothrombosis. Pharmacological control of platelet hyper-reactivity has become a cornerstone in the prevention of thrombo-ischaemic complications in atherosclerotic diseases. Current antiplatelet therapies substantially improve clinical outcomes in patients with coronary artery disease, but at the cost of increased risk of bleeding. Beyond their role in thrombosis, platelets are known to regulate inflammatory (thrombo-inflammatory) and microcirculatory pathways. Therefore, controlling platelet hyper-reactivity might have implications for both tissue inflammation (myocardial ischaemia) and vascular inflammation (vulnerable plaque formation) to prevent atherosclerosis. In this Review, we summarize the pathophysiological role of platelets in acute myocardial ischaemia, vascular inflammation and atherosclerotic progression. Furthermore, we highlight current clinical concepts of antiplatelet therapy that have contributed to improving patient care and have facilitated more individualized therapy. Finally, we discuss novel therapeutic targets and compounds for antiplatelet therapy that are currently in preclinical development, some of which have a more favourable safety profile than currently approved drugs with regard to bleeding risk. These novel antiplatelet targets might offer new strategies to treat cardiovascular disease.