Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component.