Twenty years ago, we started the characterization of a 5-HT receptor coupled to cAMP production in neurons. This receptor obviously had a different pharmacology to the other 5-HT receptors described at that time, i.e. the 5-HT 1 , 5-HT 2 , 5-HT 3 receptors. We proposed to name it the 5-HT 4 receptor. Nowadays, 5-HT 4 receptors are one of the most studied GPCRs belonging to the “rhodopsin” family. Thanks to the existence of a great variety of ligands with inverse agonist, partial agonist, agonist and antagonist profiles, the pharmacological and physiological properties of this receptor are beginning to emerge. Although some 5-HT 4 partial agonists have been on the market for gastro-intestinal pathologies, 5-HT 4 receptor drugs have still to be commercialized for brain disorders. However, since 5-HT 4 receptors have recognized effects on memory, depression and feeding in animal models, there is still hope for a therapeutic destiny of this interesting target in brain disorders.