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Since indomethacin was first marketed, some 40 years ago, the class of nonsteroidal anti-inflammatory drugs has grown larger than any other drug class in history. At present, there are at least 25 such drugs being used in the US and abroad, both clinically and in research. Despite their widespread use, their implications to health care are just beginning to be understood. The authors review updated theories on the mechanism of action, side effects, and drug interactions of nonsteroidal anti-inflammatory drug therapy. Proposed guidelines for monitoring their use are given. A more thorough understanding of the risks-to-benefits ratio is provided in an effort to achieve maximum patient satisfaction and safety.