Prostaglandins are lipid mediators produced by cyclooxygenases from arachidonic acid, which serve pivotal functions in inflammation and pain. Inhibition of their production is the major analgesic mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs)-but also the source of most of their unwanted effects. While the development of selective inhibitors of inducible cyclooxygenase (COX)-2 (so called coxibs) has greatly reduced gastrointestinal side effects, the recent disappointment about a potential cardiovascular toxicity of COX-2-selective inhibitors has boosted interest in alternative targets. The discovery of several prostaglandin synthases and of distinct prostaglandin receptors has unraveled an unforeseen diversity within the prostanoid synthetic pathway. Behavioral and electrophysiological work in particular with genetically engineered mice meanwhile provides new clues to the role of different prostaglandins, prostaglandin synthases and prostaglandin receptors in pain pathways.