The effect of a variety of non IgE-mediated stimuli on histamine release from mast cells from different locations is described. Sensory neuropeptides are shown to resemble other polycationic compounds in preferentially activating mast cells from the rat while having a limited effect on human mast cells, except possibly those from skin. Similar results were obtained with the putative non-adrenergic, non-cholinergic neurotransmitter ATP, thereby questioning the role of neuronal mast cell activation in allergy and inflammation. Bradykinin also acted selectively against rat cells while complement-derived and formylmethionyl peptides were effective against human basophils and cutaneous mast cells. The latter results may indicate a role for the skin cell in local inflammatory responses involving complement activation and in host resistance to bacterial infection. Rat mast cells and human basophils were most responsive to hyperosmolar challenge but significant effects were obtained from human pulmonary mast cells obtained by bronchoalveolar lavage. The latter cells may thus be implicated in exercise-induced asthma. The plasma substitute dextran was a specific secretagogue for the rat while morphine sulphate largely induced histamine release from human cutaneous mast cells. The latter result may account for anaphylactoid reactions to the opiate. In total these data emphasize the functional heterogeneity of mast cells from different locations and highlight the particular pharmacological properties of the skin mast cell in man.