There is now substantial evidence for the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Selective COX-2 inhibitors (coxibs) were considered attractive candidate chemoprevention agents; however, concerns over the toxicity of systemic selective inhibition have cast some doubt on COX-2 inhibition as a safe chemoprevention strategy. COX-2 can serve as a potential biomarker of tumor evaluation including prognosis. This chapter describes proposed mechanisms for the role of COX-2 in carcinogenesis, proliferation, inhibition of apoptosis, promotion of angiogenesis, enhanced invasiveness, immune modulation, and increased mutagenesis. Critical discussions focus on the use of COX-2 as a biomarker in the evaluation of neoplasm. Our chapter demonstrates that "Fecal COX-2 Assay," a novel method to detect COX-2 messenger RNA (mRNA) in feces from subjects with colorectal neoplasms, is potentially useful for colorectal cancer screening.