Acute ischemic stroke is a leading cause of death and major disability worldwide. Approximately 50% of ischemic strokes are caused by atherothrombotic occlusion of the cerebral arteries, and antiplatelets are the mainstay of secondary stroke preventative treatment. Aspirin is beneficial if given early, and short‐term treatment using aspirin and clopidogrel is increasingly used for patients with intracranial atherosclerotic disease, minor stroke, and or transient ischemic attack. However, up to 50% of patients continue to have recurrent stroke and major vascular events, which may be partly attributable to resistance to aspirin and or clopidogrel. Although the precise mechanisms are unknown, clinical and genetic factors associated with bioavailability and binding to target receptors are implicated. This narrative review begins with the concept of aspirin and clopidogrel resistance in ischemic stroke and transient ischemic attack, potential mechanisms including genetic polymorphisms, and an overview of platelet function measures and limitations. We conclude by highlighting practical issues in the management of patients with aspirin andclopidogrel resistance including the emerging interest in ticagrelor, prasugrel, and cilostazol as well as directions for future trials in transient ischemic attack and acute ischemic stroke.