Extracranial and intracranial large artery atherosclerosis is often identified as a potential etiologic cause for ischemic stroke and transient ischemic attack (TIA). Given the high prevalence of large artery atherosclerosis in the general population, optimally treating each patient to minimize future stroke risk is paramount. To optimally define treatment, as based upon the individual patient’s history, examination, and anatomical imaging findings, clinicians can compartmentalize this disease entity into four distinct clinical scenarios: 1(a) asymptomatic and 1(b) symptomatic extracranial carotid stenosis, (2) intracranial atherosclerosis, and (3) atherosclerotic vertebrobasilar disease. In this chapter, we work to provide a framework for clinicians evaluating and treating such patients.