Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of agents with similar action but diverse chemical structures and mechanism of action. There is considerable interpatient variability in the pain relief obtained from NSAIDs even when these agents belong to the same chemical family. The reasons for this interpatient variability include pharmacodynamic actions, pharmacokinetic parameters, or a combination of both. Furthermore, two distinct forms of the key enzyme cyclo-oxygenase (COX) have been identified. The constitutive enzyme COX-1 is found in most tissues and is believed to confer gastric mucosal protective action, and COX-2, the inducible enzyme, is implicated in pain and inflammation. Selective inhibition of COX-1 and COX-2 may allow prediction of drugs' major effects. By definition, NSAIDs are expected to modulate synovial inflammation present in the arthritic joints. Whether NSAIDs can positively influence the progression of arthritic disorders by modifying the underlying pathology remains to be answered. This review provides guidelines on how to choose NSAIDs rationally keeping in view the mechanism of tissue injury, the mode of action of NSAIDs, and their adverse effects.