Prostaglandin E₂ (PGE₂), a cyclooxygenase (COX) product, is the best known lipid mediator that contributes to inflammatory pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of COX-1 and/or COX-2, suppress inflammatory pain by reducing generation of prostanoids, mainly PGE₂, while they exhibit gastrointestinal, renal and cardiovascular toxicities. Selective inhibitors of microsomal PGE synthase-1 and subtype-selective antagonists of PGE₂ receptors, particularly EP₁ and EP₄, may be useful as analgesics with minimized side-effects. Protein kinase C (PKC) and PKA downstream of EP₁ and EP₄, respectively, sensitize/activate multiple molecules including transient receptor potential vanilloid-1 (TRPV1) channels, purinergic P2X3 receptors, and voltage-gated calcium or sodium channels in nociceptors, leading to hyperalgesia. PGE₂ is also implicated in neuropathic and visceral pain and in migraine. Thus, PGE₂ has a great impact on pain signals, and pharmacological intervention in upstream and downstream signals of PGE₂ may serve as novel therapeutic strategies for the treatment of intractable pain.