The discovery of H2-receptors by Black and coworkers opened a new era in the history of histaminology. Their importance became apparent when, soon after their discovery, the physiological role of histamine in the regulation of gastric secretion was clarified. In the last decade the explosion of research in the field of histamine and its receptors has demonstrated that H2-receptors have a much wider distribution than previously suspected. H2-receptors are found in the brain, the endocrine and exocrine glands, the pulmonary system, the cardiovascular system of different species, the gastrointestinal muscle, the genitourinary system, the immunological system and in the skin. In some instances stimulation of the various H2-receptors evokes responses that are opposite to those elicited by stimulation of H1-receptors. In other cases they are quite similar. Usually, activation of H2-receptors leads to an increased activity of the adenylate cyclase system with a consequent increase in intracellular cyclic AMP. Most H2-receptors are located postsynaptically on muscle or gland surfaces. However, there is recent evidence concerning the possibility of a presynaptic localization with a modulatory function on the release of different mediators. Finally, controversy exists over the possibility that H2-receptors do not represent a homogeneous population. In fact, several observations suggest that "anomalous" H2-receptors are characterized by different sensitivity to the H2-antagonists and/or antagonists in various tissues. If this is true, exact characterization of H2-receptors will be decidedly more difficult and will require "super selective" H2-agonists and antagonists which are not currently available.