5-HT4 receptors control brain physiological functions such as learning and memory, feeding and mood behaviour as well as gastro-intestinal transit. 5-HT4 receptors are one of the 5-HT receptors for which the available drugs and signalling knowledge are the most advanced. Several therapeutic 5-HT4 receptor drugs have been commercialized. Therefore, the hope that 5-HT4 receptors could also be the target for brain diseases is reasonable. Several major devastating illnesses could benefit from 5-HT4 receptors-directed therapy such as Alzheimer's disease, feeding-associated diseases such as anorexia and major depressive disorders.