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Antihistamines are systemically administered most widely in dermatology, which may be attributable to the important roles of histamines in common diseases such as urticaria and atopic eczema. Of the currently recognized four subtypes of G protein-coupled histamine receptors, only H1 and H2 subtypes are demonstrated to be expressed in human skin. Antihistamines, also named as H1-inverse agonists, not only have antihistamine activity but also have antiinflammatory effect independent of their actions on H1 receptors. Despite their wide use in dermatology, the action mechanism of antihistamines remains unclear, and additional studies are warranted.