Coronary artery disease, the major manifestation of atherosclerosis, is the leading cause of death in the Western world. However, the pathogenesis of atherosclerosis is still poorly understood. Controversy exists regarding the participation of innate immunity involving macrophages and natural killer (NK) cells vs antigen-specific acquired immunity involving lymphocytes. Macrophages predominate in atherosclerotic lesions. NK cells, although smaller in number, are present as well. Furthermore, T lymphocytes that participate in acquired immunity are frequently observed in lesions and can modulate lesion progression. By using mouse models of hyperlipidemia, our laboratory is addressing in vivo the participation of both innate inflammatory responses and acquired immune responses in atherosclerosis.