There has been significant recent interest in the cardiovascular effects of cyclooxygenase 2 (COX-2) selective inhibitors. Whereas much attention has been focused on the putative prothrombotic effect of these agents, their cardiorenal and blood pressure elevating actions may be of equal if not greater importance to cardiovascular risk. COX-2 is widely expressed throughout the kidney, and inhibition of this enzyme is contributory to reduced glomerular filtration, salt and water retention, and blood pressure elevation. The key issues in relation to COX-2 inhibitors and blood pressure are whether these blood pressure-elevating effects are similar to or differ from nonselective nonsteroid anti-inflammatory drugs, whether differences exist among COX-2 inhibitors in regard to blood pressure regulation, and if so, possible mechanisms underlying blood pressure differences between COX-2 inhibitors. With regard to the last issue, possible mechanisms include greater COX-2 selectivity of certain agents such as rofecoxib, the differing half-life of these agents, the carbonic anhydrase activity of celecoxib (which may offset renal-induced salt and water retention), and possible aldosterone modulation by rofecoxib. Finally, and perhaps most important, the issue arises as to whether blood pressure elevation may contribute in whole or in part to the increase in cardiovascular events observed with these agents in some but not all studies. Ultimately, adequately powered, prospective randomized clinical trials assessing relevant cardiovascular endpoints are required to address many of these outstanding questions. Such studies have recently been announced and will commence soon.