Serotonin (5-hydroxytryptamine, 5-HT; 1) is a major neurotransmitter that is believed to produce many of its effects via interaction at seven populations of 5-HT receptors, 5-HT1 to 5-HT7, and the serotonin transporter (SERT). Serotonin was discovered in the late 1940s, and the first 5-HT receptors were identified in the periphery shortly thereafter. It was in the 1970s that 5-HT binding sites were definitively identified in the brain, and in 1979 two populations of receptors, 5-HT1 and 5-HT2 receptors, were proposed (reviewed in ref 1). Over the ensuing decade or so, by use of techniques such as radioligand binding to brain homogenates, autoradiography, and molecular biology, seven families of 5-HT receptors were described.2 Some families consist of multiple subpopulations, excluding splice variants and species homologues, and at least 14 different types of 5-HT receptors have been reported. Nearly all these 5-HT receptors now have been cloned and expressed (see Kroeze et al.3 for a recent review of those 5-HT receptors cloned to date). Work on 5-HT receptors has led to the introduction of various agents currently in clinical use, or now in clinical trials, here and abroad. Among some of the first were the anxiolytic agent buspirone (5-HT1A partial agonist), the antimigraine agent sumatriptan (5-HT1D/1F agonist), the antipsychotic agent risperidone (5-HT2/D2 antagonist), and the antiemetic agent ondansetron (5-HT3 antagonist). Three of the newest populations of 5-HT receptors are the 5-HT5, 5-HT6, and 5-HT7 receptors. Given the enormous effort devoted to 5-HT1-5-HT4 receptors, various selective agonists and/or antagonists have been developed, and significant progress has been made toward elucidating their functional properties. In contrast, 5-HT5-5-HT7 receptors have been less extensively investigated and much less is known about them. Because these receptors could be involved in, for example, schizophrenia, convulsive disorders, memory, cognition, sensory processing, circadian rhythm, brain development, and cardiovascular function, they would seem to represent potential, yet hitherto unexploited, targets for drug development. Owing to the paucity of information on these latter receptor populations, it was not so long ago that they were collectively referred to as 'orphan serotonin receptors'. But with efforts made in the past few years, this situation is rapidly changing.