Atherosclerotic occlusive disease of the cervical and intracranial arteries leads to ischemic stroke through two separate, but interrelated, mechanisms: local thrombosis or embolism from atherosclerotic plaque, and hemodynamic failure (low flow). In this article, the author discusses the evidence linking these two mechanisms with cerebral ischemia, and the evidence for the synergistic effects of thromboembolism and impaired hemodynamics. An understanding of these two mechanisms is important because these mechanisms provide the rationale for revascularization for patients who have atherosclerotic stenosis or occlusion. In addition, the biologic imaging of atherosclerotic plaques and hemodynamic assessment eventually will play an important role in stratifying patient risk and guiding physiologically based patient selection for intervention.