1. The airway and metabolic responses to an intravenous β 2 -agonist salbutamol have been investigated in normal subjects before and after chronic administration of inhaled salbutamol, 1600 μg daily for 2 weeks. 2. Before chronic inhalation of salbutamol there was a dose-dependent increase in specific airway conductance after intravenous salbutamol in cumulative doses from 25 to 300 μg. 3. Measurement of concentrations of blood glucose, lactate, pyruvate, glycerol, ketone bodies, non-esterified fatty acids, insulin, plasma cyclic AMP and cyclic GMP were made after each increment of salbutamol and all showed an increase apart from cyclic GMP. 4. After chronic inhalation of salbutamol there was a decrease in the airway, metabolic and insulin response to intravenous salbutamol. The cyclic AMP response showed little change. 5. This study confirms the development of adrenergic resistance in the airways of normal subjects after large doses of inhaled salbutamol and shows that this is associated with widespread metabolic adrenergic resistance.