Atherosclerosis is a systemic, multifocal disease leading to a various symptoms and clinical events. Beyond disparities related to the organs involved, some differences might exist according to whether the lesions occur in the large (proximal) or small (distal) arteries. Atherosclerotic lesions occur predominantly in the large vessels first, and more distal lesions occur with aging. Proximal lesions are usually more evolving, especially with higher rates of unstable plaques in the proximal segments of coronary arteries. Racial differences regarding lesion distribution exist, with higher rates of distal lesions observed in races other than caucaians. Despite conflicting results found in each vascular territory, there is a suggestion of a stronger association between large vessel disease and smoking and dyslipidemia, whereas diabetes appears more specific for small vessel disease. Hypertension is more frequently reported in intracranial than in extracranial cerebrovascular disease. Preliminary studies report inflammatory markers preferably associated to large-vessel atherosclerosis. Proximal lesions in 1 territory are more frequently associated with concomitant lesions in other territories. Geometric, hemodynamic, and histologic particularities in large and small vessels may at least partially explain these differences, and some recent data point out different biologic properties of the endothelium according to its location.