Stroke is a leading cause of death, disability, and dependence. Treatment of patients with acute stroke requires an integrated, systematic approach with thrombolysis, if indicated, and aggressive supportive care. Subacute treatment of patients with ischemic stroke should focus on the initiation of antithrombotic therapy and prevention of secondary stroke by risk factor modification. Treatment by emergency medicine physicians, who initiate thrombolysis and begin antiplatelet agents, and modification of preexisting risk factors are critical to patient outcome. Because few patients seen in the emergency department are eligible for thrombolysis because of the narrow timeframe for receiving treatment, most patients require antithrombotic therapy with aspirin, clopidogrel, or aspirin in combination with extended-release dipyridamole (ER-DP). Although aspirin, clopidogrel, and aspirin plus ER-DP effectively reduce the risk for recurrent stroke, according to treatment guidelines, clopidogrel alone (particularly in patients allergic to aspirin) and aspirin plus ER-DP are recommended over aspirin alone. Emergency medicine physicians should be aware of the available antiplatelet agents and the importance of antithrombotic therapy for prevention of secondary stroke.