The totality of data--the vascular biology and dinical trial data available to date--support the following conclusions: if COX-2 inhibitors are to be used, they should be considered as 2nd- or 3rd-line agents. They should be used for brief periods of time among patients who are at low risk for cardiovascular events. It is worth pointing out that COX-2 inhibitors were designed initially for use in patients at risk for bleeding ulcers, to minimize gastrointestinal toxicity. Large healthcare databases show, however, that the largest growth of COX-2-inhibitor use has occurred among individuals at low risk for GI side effects. COX-2 inhibitors increase the risk for cardiovascular events. The risk differs, to some degree, across agents, and does appear to be dose related. The relationship between cardiovascular risk and duration of therapy is an important question that requires further consideration. Early risk, from the perspective of pathobiology, may differ from long-term risk. The mechanism of cardiovascular risk is multifactorial and relates to sites of COX-2 synthesis, expression within the vasculature, and related local consequences of an imbalance between thromboxane A2 and prostacyclin. Considered collectively, increased platelet aggregation, hypertension, endothelial cell dysfunction, impaired angiogenesis, and destabilization of the atherosclerotic plaque matrix are important contributors to the "prothrombotic environment." Randomized clinical trials are required to better understand the hazards among individuals at low and high risk for cardiovascular events.