Cyclooxygenase (COX) is the key enzyme in the conversion of arachidonic acid to prostanoids, lipid mediators involved in several physiological and 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. Both isoforms play fundamental roles in atherothrombosis; however, whereas the function of COX-1 in this setting is well established, the role of COX-2 remains unclear. Indeed, the intracellular pathways regulating COX-2 induction appear numerous and complicated, varying between cell types and cellular stimulus. In recent years a long series of studies has been performed with the aim of clarifying the role of COX-2 in atherothrombosis, with the major finding that the COX-2 expression pattern in arterial vessels may be associated with either protective or plaque-destabilizing phenotypes according to the downstream synthase that couples with COX-2. In this review we summarize the role of COX-2 as well as the different downstream synthases in atherosclerosis and atherothrombosis. Finally, we briefly review the controversial vascular effects on prostanoid inhibition by COX-2 inhibitors.