Considerable evidence exists that treatment with β-receptor stimulating drugs causes desensitization in several different tissues in vitro. There is also evidence that the administration of β-receptor stimulating drugs during asthma therapy leads to the development of tolerance of at least some actions of β-stimulating drugs. The present communication presents data from experiments in animals, including humans, suggesting that treatment with an oral salbutamol leads to the development of tolerance of metabolic actions of β-adrenergic stimulating drugs. Rats given salbutamol, 20 mg/kg/day, showed a decreased lipolytic response to salbutamol and to noradrenaline. By contrast, rats subjected to adrenal demedullation showed an increased lipolytic response. These results suggested that β2-adrenoceptor-stimulating drugs may cause desensitization and also that the normal circulating levels of catecholamines may be sufficient to regulate the responsiveness of the adipose tissue. The effect of a single oral dose of salbutamol was compared in 10 women not previously given salbutamol and in 13 women treated with oral salbutamol in a dose of 4 mg 4 times/day for 12–33 days preceding study. The salbutamol-induced increase in the levels of insulin, C-peptide, glucose, and glycerol were significantly reduced in those exposed to salbutamol before the test. The rise in cyclic AMP and non-esterified fatty acids was not significantly affected. There were also differences in the salbutamol-induced fall in diastolic blood pressure and in heart rate. These differences in cardiovascular responsiveness could be accounted for by a difference in the values of these parameters before the test. Our results suggest that women receiving 16 mg/day of salbutamol, i.e. a normal clinical dose of the drug sufficient to achieve relaxation of the uterus, develop tolerance to some metabolic side effects. This, and the development of tolerance to the tremorogenic effect of β-adrenoceptor-stimulating drugs, may be clinically advantageous, but the possibility exists that tolerance may develop also to some of the therapeutic actions. The literature concerning the development of tolerance to β2adrenoceptor-stimulating drugs is briefly reviewed, and some possible explanations for what appears to be an organ-selective development of tolerance is discussed.