Specific binding of [3H]mepyramine to membranes of various peripheral tissues of different species has been demonstrated. Drug specificity indicates an association with histamine H1-receptors. Of all the tissues examined brain contains the highest numbers of binding sites, while substantial levels of specific [3H]mepyramine binding are also demonstrable in some species in heart, lung, adrenal and ileum. Negligible specific [3H]mepyramine binding is observed in the liver, stomach and uterus of several species. The lesser bronchoconstricting response of the rat than of other species to histamine is paralleled by a lower number of [3H]mepyramine binding sites in rat lung than in other species. However, similar numbers or [3H]mepyramine binding sites occur in ileal membranes of rat, guinea pig and rabbit, although contractile effects of histamine vary in these species. In the quinea-pig ileum, [3H]mepyramine binding is most concentrated in the longitudinal muscle itself where histamine exerts its predominant contractile effects. In the bovine adrenal gland, [3H]mepyramine binding is more abundant and has higher affinity for drugs in the medulla than in the cortex.