Selective inhibitors of cyclooxygenase-2 (COX-2) were designed to minimize gastrointestinal complications of traditional non-steroidal anti-inflammatory drugs (NSAIDs) attributed to the suppression of COX-1-derived prostanoids. Selective COX-2 inhibitors (coxibs) are effective anti-inflammatory and analgesic drugs. However, recently it has become apparent that some coxibs increase the risk of serious cardiovascular events, including myocardial infarction and stroke. This has led to the withdrawal of rofecoxib from markets and has raised the concern about an inherent atherothrombotic risk of this class of drugs. This question should be carefully analyzed in the light of the current knowledge on COX-2 functions in the cardiovascular system. COX-2 is regarded as an inducible enzyme involved in the pathophysiology of inflammation and pain. In the cardiovascular system, COX-2 has also been associated with proinflammatory/ pro-atherogenic stages, due to its up-regulation in monocyte-derived macrophages present in atherosclerotic lesions. However, experimental and clinical studies suggest that COX-2 is “constitutively” expressed in some tissues, among them in the vascular endothelium, where COX-2-derived prostanoids, especially prostacyclin (PGI2), contribute in the maintenance of vascular homeostasis and integrity. This review provides an updated overview on the functions of COX-2 in the cardiovascular system addressing key issues that could help to understand why chronic COX-2 inhibition may have undesirable effects in patients at cardiovascular risk.