Inflammation is the response of any tissue to injury or trauma. The inflammatory response forms the basis of several pathological and pathophysiological processes, including wound healing, rheumatoid arthritis and neurodegenerative disorders, including Alzheimer's disease and stroke. The response is mediated by various signaling molecules and enzymatic pathways, among which the cyclooxygenase (COX) pathway is one of the most predominant. COX catalyzes the formation of prostaglandins and thromboxanes from arachidonic acid (AA). In 1971, Sir John Vane demonstrated for the first time that the mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is via inhibition of COX. Since the discovery of at least two isoforms of COX, inhibition of COX-2 has generally been considered the basis for the anti-inflammatory effects of NSAIDs. However, more recent studies of COX-2 have controversially postulated that the selective inhibition of COX-2 may not be beneficial, but rather can be detrimental. This is based on the observations that, during inflammation, not all AA-derived mediators are exclusively pro-inflammatory. This review will attempt to discuss the confusing and contradictory data relating to selective COX-2 inhibition and inflammation, particularly focusing on anti-inflammatory AA-derived mediators. We will also try to advance the perspective that inflammation is not just a single process, but is rather a dynamic and continuously changing event, not just in terms of time, mediators and cells, but also in the initiating stimuli, whether it be in the periphery or the central nervous system.