The classification of histamine receptors has to date been based on rigorous classical pharmacological analysis, and as yet, the classification of the three histamine receptors that have been defined by this process,(ie, the H1-, H2-, and H3-receptors) have not been added to because of more recent molecular biological approaches (Schwartz et al., 1991, 1995; Hill, 1990; Leurs et al., 1995b). The scant number of known histamine receptors, compared with the plethora of receptors for some other endogenous substances, probably reflects the relative neglect of histamine rather than a paucity of its receptors. There is some preliminary evidence of heterogeneity of the known histamine receptors (which will be reviewed later in this article), but the acceptance of additional subtypes still awaits the identification of “sequence differences” within a single species and the development of selective agonists and antagonists providing the structural, recognition, and transductional information necessary for reliable classification. The first histamine receptor antagonists (popularly referred to as the classical antihistamines but now called H1-receptor antagonists) were synthesized (Bovet and Staub, 1936; Bovet, 1950) over 20 years after the discovery (Barger and Dale, 1910) and descriptions of some of the physiological effects (Dale and Laidlaw, 1910) of histamine. These accomplishments had been preceded, as for some other endogenous biogenic amines, by its synthesis as a chemical curiosity (Windaus and Vogt, 1907). Early studies of the antihistamines were qualitative, for example, the demonstration of their ef-a Address for correspondence: Professor SJ Hill, Department of Physiology & Pharmacology, Queen’s Medical Centre, Nottingham NG7 2UH, United Kingdom.