Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a commonly used class of therapeutic agents in rheumatic disorders, especially in our elderly population. Although their mechanism of anti-inflammatory action may be multifarious, global prostaglandin blockade, especially in the elderly, is responsible for many of the recognized adverse effects. Complications of NSAID gastropathy represent the most serious adverse effect, its frequency becoming an alarming health problem. Various nephrotoxicity syndromes seen with NSAID use in the elderly are less prevalent and less often recognized. Commonest is reversible, hemodynamically mediated renal insufficiency due to prostaglandin blockade. Potential differences among NSAIDs are reviewed in light of the concept of compartmentalized renal prostaglandin blockade. A framework is developed for the clinical application of these potential differences, especially in the treatment of elderly patients. Along a continuum of increasing risk factors for NSAID nephrotoxicity or increasing NSAID dose, there likely exists an intermediate therapeutic window where differences among NSAIDs are most relevant.