In the last decade, the potential role of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in brain diseases has been extensively studied. COX-2 over-expression has been associated with neurotoxiticy in acute conditions, such as hypoxia/ischemia and seizures, as well as in inflammatory chronic diseases, including Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). However, the role played by COX-2 in neurodegenerative diseases is still controversial and further clinical and experimental studies are warranted. In addition, the emerging role of COX-2 in behavioural and cognitive functions strongly indicates that studies aimed at improving our knowledge of the physiological role of COX-2 in the central nervous system are crucial to fully understand the pros and cons of its manipulation in disabling neurological diseases.