Smoking remains the leading cause of cardiovascular disease, accounting for almost one third of cardiac deaths in the Western industrialized countries. Atherosclerosis in general, and coronary disease in particular, is now considered an inflammatory disease. Recent research has tried to better characterize the subcellular mechanisms of smoke and nicotine on the vessel wall and circulating mediators of disease. Whereas nicotine-dependent receptor activation on endothelial cells has long been considered to elicit antiinflammatory actions, recent observations reveal that nicotine evokes close interactions between the endothelium and proinflammatory cells: namely, leukocytes. Besides monocytes and macrophages, nicotine has been shown to stimulate neutrophils, a cell species long been considered irrelevant for the progression of atherosclerotic disease. Being stimulated by nicotine, neutrophils generate reactive oxygen species and release prooxidant enzymes like myeloperoxidase, which are capable of entering the vessel wall independently. Central mechanisms by which these enzymes can modulate the structural and functional integrity of the vessel wall have been characterized and increased our understanding of neutrophil-derived changes in vascular homeostasis in response to smoking and nicotine, respectively.