Chronic smoking is associated with functional and structural vascular changes underlying inflammatory processes responsible for plaque formation and rupture. Cyclooxygenase (COX) is the key enzyme linking smoking action to inflammatory damages: it is responsible for the conversion of arachidonic acid to prostanoids, and lipid mediators involved in most of pathological processes. Two COX isoenzymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, and preferential coupling to upstream and downstream enzymes. The aim of this review is to highlight the pathogenetic role of chronic smoking in vasomotor dysfunction, inflammation, and modification of lipids underlying the initiation and the progression of atherosclerosis and to remark the hypothesis that plaque composition rather than plaque size is the real determinant of the plaque evolution toward rupture and the major responsible for acute ischemic syndromes. The concomitantly higher expression of EP4, COX-2, mPGES-1, MMP-2 and MMP-9 in unstable plaques is focused and the role of PGE2 as pathophysiological link between smoking, COX-2 and MMP activity is stressed. Indeed, the intracellular pathways regulating COX-2 and the mechanisms suggested to clarify the role of COX-2 and downstream synthases in atherothrombosis are summarized.