Various nephrotoxicity syndromes are seen with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The most common is reversible, hemodynamically mediated renal insufficiency. The role of prostaglandin inhibition by NSAIDs is discussed in the context of renal prostaglandin physiology. Potential differences among NSAIDs are reviewed. The "renal sparing" effect of sulindac may be attributable to the relative preservation of renal prostaglandin synthesis. Salsalate, although anti-inflammatory, demonstrates weak prostaglandin inhibition at therapeutic doses. A framework is developed for the clinical application of these considerations. Along a continuum of increasing risk factors for NSAID nephrotoxicity, or increasing NSAID dose, there likely exists a therapeutic window where differences among NSAIDs are most relevant.