5-HT (serotonin) is a significant modulator of sensory input to the CNS, but the only analgesics that selectively target G-protein-coupled 5-HT receptors are highly specific for treatment of headache. Two recent papers in BJP shed light on this puzzling situation by showing that primary afferent neurotransmission to the superficial layers of the spinal and trigeminal dorsal is inhibited by different subtypes of the 5-HT1 receptor-5-HT 1B(and 1D)in the trigeminal dorsal horn and 5-HT1A in the spinal dorsal horn. The inputs being studied probably include nociceptive afferents, and the similarities of the methods employed in the two studies minimize the possibility that the different findings are an experimental artefact. Rather, the findings raise interesting questions about the possible anatomical or functional basis for the apparent regional selectivity of 5-HT1 receptor actions, and whether these differences could be exploited for therapy. The results also emphasize the relative lack of information we have about the molecular details of the pro- or anti-nociceptive actions of 5-HT itself on primary afferent neurotransmission.