Urticaria may develop in response to a number of stimuli such as allergic reactions, drugs, cold, pressure, stings and, most interestingly, neuropsychological upheavals. Classical treatment has utilised H1-receptor antagonists, in view of the fact that histamine released from local mast cells acts on H1-receptors on the vasculature and participates in the pathophysiology of this syndrome. More recently, H2-receptor antagonists have also been tried, alone or in combination, with encouraging results. The question still remains why H2-receptor antagonists should have any beneficial effect since H2-receptors are mostly present on exocrine cells and on T-suppressor lymphocytes, where they are stimulatory, or mast cells, where they are auto-inhibitory. Possible explanations may include the ratio of H1- to H2-receptors on local vasculature and the effect of H2-antagonists on responses elicited through nervous system activity via cholinergic or neuropeptidergic neurons. Finally, evidence is presented that certain tricyclic H-receptor antagonists may have powerful inhibitory effects on secretion from both peripheral and central nervous system mast cells, as well as from neurons. The possible role of H3-receptors in this process is also discussed. At present, the available evidence does not justify the routine use of H2-antagonists in the treatment of urticaria.