Atherosclerosis is a disease that begins in fetal life and represents a leading cause of morbidity and mortality associated with significant socioeconomic consequences. A central concept with regard to its pathogenesis is that of endothelial cell dysfunction, which is associated with the release of a large number of mediators secreted by leukocytes that are present in large numbers at the sites of atheroma formation. Neutrophil peptides defensins and cathelicidins are essential elements of the innate immunity and have been present in high concentrations in atherosclerotic plaques in humans. Recently, their role as potential mediators of vascular disease was investigated. Defensins are involved in the lipoprotein metabolism in the vessel wall, favoring LDL and lipoprotein (a) accumulation and modification in the endothelium and the extracellular matrix. They also interfere with the vascular smooth muscle cell function, exhibit prothrombotic activity, and play an inhibitory role in various phases of angiogenesis. Cathelicidins were recently found to enhance endothelial proliferation in cultures, induce functionally significant angiogenesis in animal models, and regulate endothelial cell apoptosis. Further study of these peptides could provide useful insight in the relationship between inflammation and atherosclerosis and is anticipated to have therapeutic and prognostic ramifications.