Antihistamines act by competing with histamine for H1 or H2 histamine receptors on cell membranes. In addition, most of the common antihistamines bind other receptors and thus exert other pharmacologic actions. For all practical purposes, mast cells and basophils are the main physiologic sources of histamine, and the primary usefulness of antihistamines is in diseases characterized by excessive production and release of histamine by these two cell types. Experimental models have proven useful for evaluating antihistamine compounds in humans. In these model systems, a test drug may be employed to block one or more of the known effects of exogenously administered histamine or a histamine agonist. Or the release of endogenous histamine may be brought about in a controlled fashion by agents such as allergens, opiates, or compound 48/80, and the drug's effects on this process may then be measured. In the case of the central nervous system, unfortunately, such models are not available and other means of evaluation must be devised. The dose response and duration of action of orally administered antihistamines can be determined in a simple skin model by their blocking of the wheal and erythema (flare) resulting from an intradermal challenge with histamine, an allergen, or compound 48/80. Antihistamines can also be evaluated in urticaria induced by scratching or cold. Itching that commonly follows injection of histamine or an allergen into the skin is also inhibited by this class of drugs. Most of the commonly used antihistamines are effective in these models, which form the basis for evaluating antihistamines in the treatment of skin diseases. In the nose and conjunctiva, other model strategies are used.(ABSTRACT TRUNCATED AT 250 WORDS)