The existing epidemiologic literature was comprehensively reviewed to retrieve all epidemiologic studies (case control and cohort studies) that examined exposure to traditional over the counter nonsteroidal anti-inflammatory drugs (OTC NSAIDs) and the risk of cancers of the colon, breast, prostate and lung from 1980 forward. These malignancies account for more that half of all cancer deaths in the United States and the United Kingdom. Estimates of effects (relative risks or odds ratios) and 95% confidence intervals were abstracted from these reports for meta-analysis. Regular intake of OTC NSAIDs produced highly significant composite risk reductions of 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Furthermore, in a series of case control studies, daily use of a selective COX-2 inhibitor, either celecoxib or rofecoxib, significantly reduced the risk for each of these malignancies. The evidence is compelling that anti-inflammatory agents with selective or non-selective activity against cycloooxygenase- 2 (COX-2) have strong potential for the chemoprevention of cancers of the colon, breast, prostate and lung. Results confirming that COX-2 blockade is effective for cancer prevention have been tempered by observations that some selective COX-2 inhibitors pose a risk to the cardiovascular system. Nevertheless, meta-analysis of independent estimates from 72 studies provides no evidence that the selective COX-2 inhibitor, celecoxib, influences the relative risk of cardiovascular disease (composite relative risk = 0.98, 95% CI = 0.88–1.10). Molecular studies reveal that over-expression of COX-2 is a prominent feature of premalignant and malignant neoplasms. Evidence is accumulating that carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of COX-2 and the prostaglandin cascade in the “inflammogenesis of cancer”.