In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.