Background: Clinicians frequently ascribe lacunar strokes to lipohyalinosis/arteriosclerosis, but classic neurovascular pathology studies lacunar infarcts are more often due to “microatherosclerosis” (small atheromatous plaque within penetrating arteries). The proportion of lacunar infarcts in clinical practice due to microatherosclerosis has not been previously quantified. Methods: The findings in all reported neuropathologic studies were catalogued for the 4 lacunar syndromes of pure motor hemiparesis (PMH), pure sensory stroke (PSS), dysarthria-clumsy hand (DCH), and ataxic hemiparesis (AH). Systematic meta-analyses, per PRISMA guidelines, were performed of large clinical series of consecutive ischemic stroke patients to delineate: 1) the proportion of all ischemic strokes due to lacunar infarcts, and 2) among the lacunar events, the relative frequencies of PMH, PSS, DCH, and AH. Results: Neuropathology showed: PMH caused by microatherosclerosis in 64%, parent artery ostial atherosclerosis in 7%, lipohyalinosis in 14%, and embolism in 14%; PSS caused by lipohyalinosis in 100%; DCH caused by embolism in 100%; and AH caused by microatherosclerosis in 100%. In the systematic review, among 22 large ischemic stroke series enrolling 25,260 patients, frequency of lacunar infarct was 18.8% (±5.1%). Among 5 large series enrolling 838 lacunar infarct patients, subtype frequencies were: PMH 45.5%, PSS 17.7%, DCH 7.4%, and AH 2.9% (with the remainder sensorimotor stroke and less common lacunar syndromes). Quantitative synthesis indicated that, among lacunar strokes, microatherosclerosis is the most common cause (44%), followed by lipohyalinosis (33%), and parent artery athero or embolism (combined 23%). Among all ischemic strokes, microatherosclerosis is the cause in 6%. Conclusion: Microatherosclerotic plaque within a penetrating artery is a common cause of cerebral ischemia, accounting for 6% of all ischemic strokes. This substantial burden of microatherosclerosis is the likely pathophysiologic basis for the benefits of thrombolytic and statin therapy in lacunar ischemic stroke.