This review examines the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), both traditional NSAIDs and cyclooxygenase-2 selective inhibitors (COXIBs). It describes the history of traditional NSAIDs and the development of COXIBs to explain why their cardiovascular side effects were unnoticed for many decades. Further, the review presents the mechanism of action of NSAIDs, to elucidate the possible underlying basis for why they are associated with an increased risk of cardiovascular disease. Finally, data on the cardiovascular risk with NSAID use in patients with rheumatoid arthritis are presented, and we propose possible explanations for why the risk of cardiovascular side effects in these patients seems to be less pronounced than in the general population.