Atherothrombosis is the common underlying process for numerous progressive manifestations of cardiovascular disease, including coronary artery disease (CAD) and cerebrovascular disease (CVD). Antiplatelet therapy is the cornerstone of pharmacological management in patients with atherothrombosis. Over the past 20 years, major advances in antiplatelet pharmacotherapy have been made, particularly for the treatment of patients with CAD. The treatment of patients with concomitant CAD and CVD is complex, owing to their increased risk of both ischaemia and bleeding. When CVD arises from large artery atherosclerosis, antithrombotic therapies are essential to prevent stroke or transient ischaemic attack (TIA). However, the use of antithrombotic medications in patients with CVD can put them at high risk of intracranial haemorrhage. As such, the risk-benefit profile of various combinations of antiplatelet agents in patients with both CAD and CVD is uncertain. This Review provides a state-of-the-art account of the available evidence on antithrombotic therapies for the secondary prevention of atherothrombotic events in patients with concomitant CAD and CVD, particularly those with a history of noncardioembolic stroke or TIA.