Several epidemiological, clinical and experimental studies established nonsteroidal anti-inflammatory drugs (NSAIDs) as promising cancer chemopreventive agents. Long-term use of aspirin and other NSAIDs has been shown to reduce the risk of cancer of the colon and other gastrointestinal organs as well as of cancer of the breast, prostate, lung, and skin. Understanding the action of NSAIDs provides substantial insights into the mechanisms by which these unique agents regulate tumor cell growth and enable better strategies for prevention and treatment. NSAIDs restore normal apoptosis and reduce cell proliferation in human adenomatous colorectal polyps, experimental colonic tumors, and in various cancer cell lines that have lost critical genes required for normal function. NSAIDs, particularly selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib, have been shown to inhibit angiogenesis in cell culture and in rodent models of angiogenesis. Exploration of the multistep process of carcinogenesis has provided substantial insights into the mechanisms by which NSAIDs modulate these events. However, unresolved questions with regard to safety, efficacy, optimal treatment regimen, and mechanism of action currently limit the clinical application of NSAIDs to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective NSAIDs for chemoprevention is complicated by the potential that rare, serious toxicity may offset the benefit of treatment with these drugs given to healthy individuals who have a low risk of developing the disease. Growing knowledge in this area has brought about innovative approaches using combine actions of NSAIDs with other agents that have different modes of action. It has also led to the development of nitric oxide-releasing NSAIDs, that induce tumor cell apoptosis and compensate for COX function, as a means of increasing efficacy and minimizing toxicity. There is growing optimism for the view that full exploration of the role of NSAIDs in the prevention and treatment of epithelial cancers will serve towards reducing of mortality and morbidity from various cancers.