There are various substances that mediate or modulate pain, but most of the studies have been in human skin or in laboratory animals. It is not known whether the same substances are involved in the pain of bone metastases, and the tentative conclusions made here are by extrapolation and by inference from the effects of drugs whose actions have been characterized. Prostaglandins E2 and I2 cause hyperalgesia to bradykinin and histamine, and they increase oedema formation. Other lipids may also have a similar potentiating role in pain and inflammation. Pain can be sensed from the periosteum, and from within the bone due to increased pressure. NSAIDs act mainly at peripheral sites to inhibit the formation of prostaglandins, and so lessen the hyperalgesia and oedema production, but a central inhibition of prostaglandin synthesis may also contribute to the analgesia. Opioid peptides have important roles in pain, mainly as analgesic substances, but in contrast some may have a role as algesic agents by an action on different receptors. The importance of these and other possible mediators and modulators of pain has not been fully assessed, but advances will be made when selective antagonists of lipoxygenases and kinins become available for use in humans.