Histamine, a ubiquitous cell-to-cell messenger, exerts its numerous actions through interaction with three pharmacologically distinct receptor subtypes, termed H1, H2 and H3. The design of selective agonists and antagonists has allowed to establish their respective pharmacological profile. Radioligand binding studies and, very recently, molecular biological studies have shown that they all belong to the superfamily of G-protein coupled receptors. H1 and H2-receptor antagonists have been successfully used for a long time in the treatment of allergy and ulcer, respectively. Some of them have been designed as highly potent and selective radioligands and have allowed to analyze the precise distribution of H1 and H2 receptors in various tissues including the brain. Recently, H1- and H2-receptor genes have been cloned in various animal species. Transfection of mammalian cells with these intronless genes has confirmed the respective coupling of H1 and H2 receptors with phospholipase C and adenylylcyclase. However, other known or unknown intracellular signals, could also be triggered by the stimulation in a transfected cell of a single H1 or H2 receptor through coupling to different G-proteins. A third histamine receptor subtype, the H3 receptor was evidenced in rodent and human brain by the inhibition of histamine release and synthesis it mediates in various areas. Thus, H3 receptors were considered as autoreceptors localized on histaminergic terminals. With the design of several potent and selective H3-receptor agonists and of an antagonist thioperamide, the critical role of H3 receptors in the control of histaminergic neurons in vivo was established.(ABSTRACT TRUNCATED AT 250 WORDS)