PROSTAGLANDINSand glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism^1,2. Two isoforms of the membrane protein COX are known³: COX-1, which is constitu-tively expressed in most tissues, is responsible for the physiological production of prostaglandins⁴; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells⁵, is responsible for the elevated production of prostaglandins during inflammation^6,7. The structure of ovine COX-1 complexed with several NSAIDs has been determined^8–10. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 Åresolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.