This review attempts to define the early events that lead to lesions of human atherosclerosis based on careful morphological studies in human autopsy specimens. In contrast to most small laboratory animals, diffuse intimal thickening (DIT) is present in human arteries before atherosclerosis develops, particularly in the atherosclerosis-prone arteries such as coronary arteries and abdominal aorta. In the earliest stage of atherosclerosis, lipids deposit eccentrically in the deep layer of DIT to form Type I lesions. These layers are enriched in extracellular matrix (ECM) proteoglycans such as biglycan. Following lipid deposition, macrophages appear in these regions and foam cells are observed (Type II lesions). Such observations support the ‘response-to-retention’ hypothesis that states that a principle early event in the pathogenesis of human atherosclerosis is the trapping and retention of lipoproteins by ECM proteoglycans followed by infiltration and accumulation of macrophages.