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This chapter describes the mechanisms of ischemia in in situ vascular occlusive disease. Cerebral blood flow below critical levels is the most important factor responsible for brain damage in patients with ischemic stroke. In patients with in situ vascular occlusive disease, stroke is most commonly caused by atherosclerosis. Two basic mechanisms can explain the vast majority of episodes of focal cerebral ischemia due to in situ vascular disease: vascular thrombosis or other condition resulting in narrowed vessel lumen and limitation of flow, and thrombus fragmentation at a vessel resulting in embolic occlusion of a distal vessel. In most patients, a thorough general physical and neurological exam can determine the presence of vascular risk factors, evidence of atherosclerosis in other organs, the vascular territory involved, and the nature of the occlusion. Lacunar syndromes reflect ischemia caused by occlusion of small vessels secondary to lipohyalinosis. Diagnostic studies demonstrate the presence of narrowing of the vessel lumen. Tests used for this purpose are ultrasound studies, magnetic resonance angiography, and catheter-requiring arteriography.