This paper briefly reviews the pharmacologic effects of nonsteroidal antiinflammatory drugs (NSAIDs) that influence the risks and benefits of using these drugs prophylactically for cancer. It describes the metabolism of arachidonic acid through the cyclooxygenase (COX) pathway, the physiologic functions ofprostanoids (prostaglandins, prostacyclin, and thromboxane A2) produced by this pathway, and the pharmacologic consequences of blocking the enzymatic activity of the two COX isoforms. We mention other proposed mechanisms by which NSAIDs may directly or indirectly affect non-COX pathways. The diverse pharmacologic effects of NSAIDs, when combined with the relatively low probability that an individual with average risk will develop any single type of cancer over a lifetime, severely limit the tolerance for toxicity if aspirin or related drugs are to be administered prophylactically to large numbers of otherwise healthy people. Further research is needed to identify a drug, dose, treatment regimen, and patient population(s) where the benefits of prophy- lactic treatment will exceed the risks. A singular advantage of aspirin over all other NSAIDs is the potential to combine reduced risk of certain cancers with cardiovascular benefit. However, many elements that are needed to achieve this remain unresolved.