The optimization of antithrombotic therapy for acute stroke treatment and secondary prevention is an evolving process based on an increasing array of studies that provide an evidence-based approach. Options have increased dramatically with the release of the non-vitamin K oral anticoagulants and with the results of recent randomized clinical trials designed to assess potential benefits versus risks for patients in an individualized fashion. Recent studies have provided important information to guide choice and dosing of antiplatelet agents as well as the length of treatment. Anticoagulant use is particularly pertinent for stroke prevention in patients at higher risk of atrial fibrillation and may have a place in certain other stroke mechanisms. One important focus of study is the potential benefit of combined antiplatelet and anticoagulant therapy. Options for our patients, when the initial choice of therapy does not demonstrate benefit or is not well tolerated, clearly, are valuable. For example, short-term dual antiplatelet therapy for minor stroke and transient ischemic attack is being adopted, but with the recognition that longer-term combined therapy is not worth the increased risk of bleeding. Alternative antiplatelet choices, such as cilostazol and possibly ticagrelor, may be of benefit for refractory patients and this could affect the decision-making process. This review represents an effort to incorporate the information from more recent stroke prevention and treatment studies with information gleaned from prior studies.