Intracranial atherosclerosis is responsible for a significant number of strokes. Medical therapy for this condition may fail, leaving patients at high risk for cerebral infarction and death. With advances in endovascular techniques on the horizon, understanding the prognosis of conservative treatment is essential for appropriate patient management. Although several small studies have attempted to address this issue, a comprehensive review regarding the natural history of intracranial atherosclerosis in a vessel-specific manner is lacking. Owing to heterogeneity in vascular anatomy and physiology, atherosclerosis in different vessels may represent diseases with fundamentally distinct courses. Therefore, it is important to distinguish vascular territories when studying the natural history of this condition. To this end, we critically review the literature investigating medical management of patients with intracranial atherosclerosis, segregating our findings by vessel. Analysis by this method suggests that middle cerebral artery atherosclerosis carries a lower mortality rate than stenoses involving other intracranial vessels, and that asymptomatic disease follows a more benign course. In addition, plaque progression and transcranial Doppler-detected microemboli seem to predict outcome according to limited data. This comprehensive review may help guide clinical decision-making and therapeutic developments in this patient population.