Thanks largely to the study of the brainstem nuclei that mediate stimulation analgesia, the involvement of the monoamines in the descending control of pain is now well established. The periaqueductal grey, the raphe nuclei (NRM and DRN) and the locus coeruleus are all key brainstem sites for the control of nociceptive transmission in the spinal cord. Although the initial emphasis was on 5-HT as the transmitter mediating this control at spinal levels, it is clear from more recent work that NA has an equally important part to play. How (or even if) the two amines differ in their roles and actions in analgesia is, however, still an open question. The small size and complexity of the brainstem areas from which analgesia may be elicited by electrical stimulation complicates the interpretation of the data. Stimulating currents may spread to surrounding regions mediating opposite effects to that of the main region stimulated. Opiates and GABA are clearly involved in descending control at both brainstem and spinal levels, although the relative roles of the different types of amino-acid and opiate receptors is still hotly debated. Despite the fact that the first report on stimulation analgesia appeared more than a quarter of a century ago in 1969, the precise connections and cord synaptology are still the basis of ongoing research. It is perhaps ironic, in an issue dedicated to new molecules and mechanisms, that those transmitters most involved in descending inhibition should be such old and familiar friends.