Although the coxibs have demonstrated superior gastrointestinal safety compared to traditional non-selective NSAIDs, questions remain regarding their effects on the renal and cardiovascular systems. In terms of renal function, both Type 1 and Type 2 cyclooxygenase (COX-1 and COX-2) are expressed constitutively in the kidney. Prostaglandins do not play a major role in the maintenance of renal function in healthy individuals but they become profoundly important in certain clinical situations such as renal stress, or volume depletion. In such situations the effects of the coxibs and non-selective NSAIDs are likely to be similar. The incidence of renal side effects is low (1-5%) and the patients at risk of renal complications are well defined and can usually be identified prospectively and followed up as appropriate. From the cardiovascular point of view, questions have been raised as to whether the coxibs have a prothrombotic effect. Here we review the available evidence and consider various hypotheses for an apparent increase in cardiovascular events reported in one coxib study (the VIGOR trial). Because of a lack of anti-platelet activity, coxibs are not suited for the provision of cardiovascular prophylaxis, and in patients at risk of myocardial infarction the prophylactic use of aspirin should always be considered. Although evidence suggests that use of coxibs with low-dose aspirin is safer than the combination of traditional NSAIDs with aspirin, further studies are required to confirm that this is the case.