Cyclooxygenase (COX) enzymes, or prostaglandin-endoperoxide synthases (PTGS), are heme-containing bis-oxygenases that catalyze the first committed reaction in metabolism of arachidonic acid (AA) to the potent lipid mediators, prostanoids and thromboxanes. Two isozymes of COX enzymes (COX-1 and COX-2) have been identified to date. This review will focus specifically on the neurobiological and neuropathological consequences of AA metabolism via the COX-2 pathway and discuss the potential therapeutic benefit of COX-2 inhibition in the setting of neurological disease. However, given the controversy surrounding the use of COX-2 selective inhibitors with respect to cardiovascular health, it will be important to move beyond COX to identify which down-stream effectors are responsible for the deleterious and/or potentially protective effects of COX-2 activation in the setting of neurological disease. Important advances toward this goal are highlighted herein. Identification of unique effectors in AA metabolism could direct the development of new therapeutics holding significant promise for the prevention and treatment of neurological disorders.