Opiates have long been known to cause the release of histamine from mast cells, resulting in several undesirable effects, such as hypotension, urticaria, pruritus, and tachycardia. The mechanism of this opiate response has remained unclear, although it is known to be non-immunological in nature. A survey of the histamine-releasing properties of a variety of opiates shows that the pharmacology of opiate-induced histamine release from mast cells is distinct from that of known opiate receptors. Although functional opiate receptors may exist on mast cells and may be capable of modulating IgE-mediated histamine release, there is no evidence that these receptors account for opiate-induced histamine release. Since other basic compounds have been suggested to release histamine from mast cells by directly activating G-proteins, it seems possible that morphine and endogenous opiates may also share this mechanism.