Although the 5-HT(5) receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The G(i)/G(0)-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT(1) receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT(5) receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological effects, thus its ligands are potential drug candidates in various areas, e.g. anxiety, sleep, incontinence, food intake, learning and memory, pain or chemoreception pathways. These findings have motivated several institutes and pharmaceutical companies to participate in the research of this field. Despite extensive research, no selective agonist and only two selective antagonists have been identified until now. Beyond these compounds, the present review provides a complete overview on all other published 5-HT(5A) receptor ligands as well as on the structure, function, distribution, genetics and possible therapeutic applications of this receptor.