1. The long-acting β 2-adrenoceptor agonist formoterol (10 -10-10 -6 M) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective β-adrenoceptor agonist isoprenaline. By contrast, the long-acting β 2-adrenoceptor agonist salmeterol (10 -10-10 -6 M) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2. Isoprenaline, formoterol and salmeterol (all at 10 -5 M) increased total cell cAMP levels in mast cells over basal by 361±90 (P<0.05), 321±89 (P<0.05) and 64±24% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10 -6 M) or salmeterol (10 -6 M) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10 -6 M) or the short-acting β 2-adrenoceptor agonist salbutamol (10 -6 M). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for β 2-adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E 2, a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5. Radioligand binding studies were performed to determine β 2-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10 -6 M) reduced β 2-adrenoceptor density by 13±5 (P>0.05), 49±13 (P<0.05) and 35±17% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to β 2-adrenoceptor-mediated responses in mast cells.