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.