This chapter discusses the role of oxidized low-density lipoprotein (LDL) in the genesis of arteriosclerosis. The anatomy of arterial walls determines the distribution of oxygen. In large arteries, the endothelial surface is in contact with highly oxygenated blood, but the media is largely avascular and dependent on oxygen diffusion from endothelium and adventitial vasa vasorum. Exposure of LDL to free radicals leads to lipid peroxidation and to a progressive loss of vitamin E and carotenoid within 6 hours. Thereafter, the polyunsaturated fatty acids 18:2 and 20:4 are degraded in a lipid-peroxidation process and a large variety of aldehydes is formed—4-hydroxyhexanal, 4-hydroxyoctenal, 4-hydroxynonenal, propanal, butanal, pentanal, hexanal, 2,4-heptadienal, and malonaldehyde (MDA). Oxidized LDL is toxic toward endothelial cells, smooth muscle cells, and fibroblast. The oxidation of LDL results in an activation of a previously masked phospholipase A 2 activity of apo B that releases the lysophosphatides and oxidized fatty acids.