The serotonin (5‐HT) system is reviewed starting from the early history of 5‐HT. There is a review of the biosynthesis, degradation, and synaptic reuptake of 5‐HT as well as the neuroanatomy of the 5‐HT system. The roles of these pathways in disease and therapeutic interventions are discussed. The focus of this chapter is on the multiple 5‐HT receptors, their history, anatomical and subcellular localization, signaling pathways, and importance in behavior, neuropsychiatric disorders and psychopharmacology.