Antithrombotic therapy is clearly beneficial in the treatment of acute myocardial infarction, but the optimal regimen is controversial. Treatment with aspirin leads to substantial and significant reductions in rates of mortality, reinfarction and stroke in patients with acute myocardial infarction, and the benefits are additive with those of thrombolytic therapy. It is unclear whether heparin confers additional net benefits over aspirin alone. In patients receiving aspirin and thrombolytic therapy, there is no mortality benefit from adding delayed subcutaneous heparin, no consistent patency benefit from adding immediate intravenous heparin and no reduction in mortality from adding immediate intravenous heparin, at least for patients treated with streptokinase. However, heparin is consistently associated with increased rates of intracranial and other serious bleeding events when used with both aspirin and thrombolytic therapy. Existing data support the need for further large-scale trials of current and newer antithrombotic regimens in acute myocardial infarction to assess the balance of benefits and risks of these regimens compared with that for aspirin alone. In patients not receiving thrombolytic therapy, randomized trial data are currently insufficient to adequately compare the benefits and risks of adding heparin to aspirin alone. The First American Study of Infarct Survival (ASIS-1) will directly compare the balance of risks and benefits of aspirin alone, aspirin plus intravenous heparin and aspirin plus intravenous hirudin in patients with acute myocardial infarction not receiving thrombolytic therapy.