Prostanoids produced by the arachidonic acid pathway play an important role in multiple stages of carcinogenesis and progression of cancer. Cyclooxygenase (COX), which exists in 2 isoforms, is the rate-limiting enzyme in the COX pathway. Cyclooxygenase-1 is constitutively expressed in normal tissues and is essential for several important physiologic functions. Cyclooxygenase-2 is selectively overexpressed in neoplastic and inflammatory tissues. Non-small-cell lung cancer (NSCLC), especially adenocarcinomas, overexpress COX-2, which contributes to the progression of malignancy by several mechanisms. This represents the basis of therapy with COX-2 inhibitors. Cyclooxygenase-2 inhibitors, which are currently in clinical use for the management of inflammatory arthritis, are well tolerated by patients. They exhibit anticancer activity by several mechanisms including induction of apoptosis, inhibition of angiogenesis, and decreased invasiveness and metastatic potential. These effects have been documented in several preclinical studies. Clinical efficacy of COX-2 inhibitors in the treatment of NSCLC is presently undergoing evaluation.