The introduction of selective cyclooxygenase-2 inhibitors offered the promise of similar efficacy in pain control without the gastrointestinal effects associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs). By blocking prostacyclin formation but leaving platelet-derived thromboxane A2 generation unopposed, there is concern that the potential gastrointestinal benefit of cyclooxygenase-2-selective inhibitors may come at the cost of increased thrombotic risk. However, the differential effects of coxibs on blood pressure, endothelial function, oxidative stress, tissue factor expression, vascular smooth muscle proliferation and neointimal hyperplasia indicate a distinct heterogeneity among this class of drugs. Importantly, the observation of an excess cardiovascular risk with traditional NSAIDs in randomized clinical trials, meta-analysis and large-scale observational studies further highlights the need to scrutinize the entire class of anti-inflammatory drugs, including traditional NSAIDs, as rigorously as coxibs.