We comprehensively reviewed the published scientific literature on non-steroidal anti-inflammatory drugs (NSAIDs) and cancer and evaluated results based upon epidemiologic criteria of judgment: consistency of results, strength of association, dose response, molecular specificity, and biological plausibility. Sufficient data from 91 epidemiologic studies were available to examine the dose response of relative risk and level of NSAID intake for ten human malignancies. Dose response curves were fitted by exponential regression. Results showed a significant exponential decline in the risk with increasing intake of NSAIDs (primarily aspirin or ibuprofen) for 7-10 malignancies including the four major types: colon, breast, lung, and prostate cancer. Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63% for colon, 39% for breast, 36% for lung, and 39% for prostate cancer. Significant risk reductions were also observed for esophageal (73%), stomach (62%), and ovarian cancer (47%). NSAID effects became apparent after five or more years of use and were stronger with longer duration. Observed protective effects were also consistently stronger for gastrointestinal malignancies (esophagus, stomach, and colon). Results for pancreatic, urinary bladder, and renal cancer were inconsistent. Initial epidemiologic studies of malignant melanoma, Hodgkin's disease, and adult leukemia also found that NSAIDs are protective. A few studies suggest that ibuprofen has stronger anticancer effects than aspirin, particularly against breast and lung cancer. Overexpression of cyclooxygenase-2 (COX-2) and increased prostaglandin biosynthesis correlates with carcinogenesis and metastasis at most anatomic sites. Preclinical investigations provide consistent evidence that both selective and non-selective NSAIDs effectively inhibit chemically-induced carcinogenesis of epithelial tumors. This review provides compelling and converging evidence that regular intake of NSAIDs that non-selectively block COX-2 protects against the development of many types of cancer.