Cerebrovascular disease is a leading cause of mortality and disability worldwide. It is characterized by an increasing prevalence and imposes a significant economic burden on healthcare systems. Stroke, which can be ischemic or hemorrhagic in nature, may be due to different etiologies, while transient ischemic attack (TIA) is due to ischemic causes and is frequently regarded as a precursor to ischemic stroke. In this context, antithrombotic therapies—particularly antiplatelet agents—play a pivotal role in acute treatment and primary and secondary prevention of TIA and ischemic stroke. Aspirin, clopidogrel, ticagrelor, and cilostazol are some of the most investigated antiplatelet drugs in this field, either in monotherapy or in combination. Over the last decades, a paradigm shift occurred, implying a more personalized pharmacological approach, tailored to pathophysiology, genetic factors, individual risk profiles, specific conditions and comorbidities, and underlying stroke etiology. Of note, different types of ischemic stroke can be distinguished, including those from large-artery atherosclerosis, small-vessel disease, cardioembolism, strokes of other determined etiologies, and cryptogenic strokes. There is a strong link between the etiological subtype of stroke and the preferred antithrombotic regimen, with antiplatelet agents playing a central role. In stroke from large-artery atherosclerosis, the benefit of dual antiplatelet is higher during the first few weeks following ischemic stroke, with a subsequent offset of the effect due to the increase in the rates of major bleeding. More uncertainty is present with regard to stroke from small-vessel disease, where the efficacy of antiplatelet drugs is still a matter of debate, and cilostazol emerged as a promising option. The most challenging scenario is probably represented by cryptogenic stroke and embolic stroke of undetermined source (ESUS), where multiple sources of embolism can be present, some of which are more responsive to antiplatelet therapy than anticoagulants. This chapter summarizes current evidence on antiplatelet therapy for acute treatment, and primary and secondary prevention of TIA and ischemic stroke, with a focus on the adoption of different regimens according to the etiological subtypes of stroke.