Aspirin (acetylsalicylic acid) is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. It affects a single pathway in the platelet activation process and provides incomplete protection against cardiovascular events. Adenosine diphosphate receptor antagonists, by blocking an alternate pathway of platelet activation, are slightly more effective than aspirin in reducing serious vascular events in patients at high risk, with similar results for the subset of transient ischaemic attack/ischaemic stroke patients. Clopidogrel is an effective and safe alternative in patients who do not tolerate aspirin, in diabetics, in hypercholesterolaemic patients, or in those with a previous history of cardiac surgery. Moreover, antiplatelet combination therapy using agents with different mechanisms of action is an attractive preventive approach. In this way, dipyridamole combined with aspirin is being tested in the European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) in cerebrovascular disease patients. Clinical and preclinical studies have demonstrated that therapy with clopidogrel and aspirin provides synergistic antiplatelet effects. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and PCI-CURE trials demonstrate the benefit of this combination therapy in patients who suffer from unstable angina or non-Q-wave myocardial infarction treated or not by percutaneous coronary intervention. The relative risk reduction in ischaemic events in long-term use was 20%. This antiplatelet regimen was safe and well tolerated. Currently, this therapeutic option is tested in individuals with ischaemic stroke in the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischaemic Attacks or Ischaemic Stroke (MATCH) Trial.