Selective cyclooxygenase-2 (COX-2) inhibitors have provided relief for patients suffering from chronic pain and other inflammatory conditions and have reduced adverse gastrointestinal effects. The documented reduction in gastric erosions, ulcerations, and perforations during the use of COX-2-selective inhibitors raises the question: would the kidney be similarly spared? Our understanding of these enzyme isoforms in the kidney is incomplete. However, kidney tissue seems to possess “constitutive” or homeostatic COX-2 enzyme, suggesting a role for prostaglandins produced by this isoform. In addition, studies evaluating the renal effects of the selective nonsteroidal anti-inflammatory drugs (NSAIDs) are inconclusive, and available data on the renal effects of COX-2-selective inhibitors are conflicting. Inadequate numbers, varied baseline patient characteristics, and different doses and lengths of drug treatment hampers comparison of the small number of clinical investigations available for review. Therefore, this article reviews the role of cyclooxygenase enzyme activity and associated prostaglandins in the kidney and the adverse renal effects of nonselective NSAIDs. We also touch on the COX-1/COX-2 selectivity of NSAIDs, the localization of COX enzymes in kidneys, and clinical studies examining the renal effects of selective COX-2 inhibitors.