Atherosclerosis is a chronic inflammatory disease. Many studies and observations suggest that it could be caused by an immune reaction against autoantigens at the endothelial level, the most relevant of which are oxidized LDL and heat shock proteins (HSP) 60/65. Endothelial dysfunction plays a fundamental role. The first antigen is related to the increased leakage and oxidation of LDL; the second to cellular reaction to stress. Experimental and clinical observations confirm the pathogenetic role of these antigens. Both innate and adaptive immunity and impaired regulatory mechanisms of the autoimmune reaction are involved. Different triggering factors are examined: infectious agents, smoking, air pollution, diabetes and hypercholesterolemia. Analogies and differences between systemic atherosclerosis and transplant-related coronary atherosclerosis help to understand their respective nature. Immune mechanisms might be responsible for the passage from stable plaque to unstable and rupture-prone plaque. Finally, prospects of treatment and prevention are linked to the induction of tolerance to responsible antigens, activation of immune regulatory response and the use of immunomodulatory drugs.