Use of nonsteroidal anti-inflammatory drugs has been shown to result in a 40% to 50% reduction in the relative risk of developing colorectal cancer. Cyclooxygenase-2 (COX-2) overexpression occurs in 43% of human invasive breast cancers and 63% of ductal carcinomas in situ. There is considerable in vitro, animal model, and epidemiologic evidence to suggest that COX-2 may play some role in breast tumor initiation and progression. PGE(2) is a major downstream mediator of COX-2 that promotes cellular proliferation and angiogenesis, makes cells resistant to apoptosis, enhances invasiveness, and modulates immunosuppression. COX-2 and COX-2-derived PGE(2) may be involved in mammary carcinogenesis. Therefore, COX-2 selective inhibitors may have a role in breast cancer prevention.