Serotonin (5-hydroxytryptamine; 5-HT), an endogenous and ubiquitous monoamine, has become a subject of "explosive" research. Though its vasoconstrictor properties were first noticed in defibrinated or clotted blood, 5-HT was discovered 75 years later going through several denominations such as "enteramine, serotonin or 5-HT". Once confirmed that serotonin, enteramine and 5-HT were the same substance, the compound was synthesized and efforts with a view to analyze 5-HT receptors were performed. On the basis of the actions of 5-HT and other drugs on several smooth muscle experimental preparations, it was originally suggested that 5-HT could act via different receptors. Thus, Gaddum and Picarelli proposed the "D" and "M" classification based on the differential sensitivity of guinea pig ileum 5-HT-induced contraction to some drugs. Later on, this classification was confronted with the new Peroutka's 5-HT, and 5-HT2 classification derived from radioligand binding studies. Since these 5-HT receptors were being referred to by many names, an international committee formulated some criteria for the characterization and a framework for the nomenclature of 5-HT receptors into 5-HT1, 5-HT2 and 5-HT3 categories. More recently, functional evidence unrelated to activation of the above 5-HT receptor types was given and a new 5-HT (5-HT4) receptor was proposed to exist. From this stage, molecular biologists have been cloning several 5-HT receptors which are different from the various receptors (sub)types characterized thus far. This review is focused on the discovery of 5-HT and the evolution of the classification of 5-HT receptors, from historical remarks to the modern concepts about receptor characterization; furthermore, the relevance of this development to medical research is considered.