Summary In cats anaesthetized with pentobarbitone, the fluid spaces in and around the brain stem were perfused from the third ventricle to the foramen magnum with artificial cerebrospinal fluid (c.s.f.) flowing usually at the rate of 5 ml/minute. Test solutions were substituted for the artificial c.s.f. without switching artifact for periods varying from 5 to 60 seconds. Observations were made on respiratory excursions, end‐expiratory % CO2 and arterial blood pressure. Perfusion with sucrose solution equiosmolar with the c.s.f. produced no respiratory or cardiovascular response. Replacement of sodium with potassium (60 to 133 mm) resulted in a prompt but mild respiratory stimulation and a delayed fall in blood pressure associated with a slowing of the heart beat. Replacement of sodium with magnesium (40 to 131 mm) resulted in a late prolonged apneustic depression of breathing and in an early but slight reduction in blood pressure. Procaine (1 to 50 mg/ml) elicited a respiratory response similar to that of excess magnesium; however, an initial rise in blood pressure to as high as 200 mmHg was evoked with procaine. Nicotine (0·05 to 0·5 mg/ml) produced an immediate brief bradypnea followed by a vigorous and slowly reversing hyperpnea accompanied most often by a fall in blood pressure. Tachyphylaxis was observed in the response to nicotine. Noradrenaline (0·001 and 0·1 mg/ml) did not produce any effect, and it did not alter the responses elicited by procaine and nicotine given by perfusion either simultaneous with or subsequent to the noradrenaline. Acetylcholine (0·5 mg/ml) produced weak transient respiratory stimulation and a small fluctuation in blood pressure which disappeared in repeated tests. Methacholine (1 mg/ml) caused a brief hyperpnea and a fall in blood pressure both of which were abolished after atropine (0·2 mg) was injected into the third ventricle. Pilocarpine (10 mg/ml) elicited no change in respiration or blood pressure. Respiratory and cardiovascular effects produced by strychnine (1 mg/ml) were attributable nonspecifically to convulsive movements of the animal. Ethamivan (1 mg/ml) produced a single deep breath and a slowly reversing rise in blood pressure. Cyanide (0·5 mg/ml) barely stimulated the respiration but it produced a long lasting rise in blood pressure. Ethyl alcohol (0·1 ml/ml) elicited brisk though brief respiratory stimulation and a short lasting fall in blood pressure. It was shown that the effects of procaine and nicotine were not qualitatively altered when the perfusion effluent was collected through a ventral craniotomy instead of the cisterna magna. It is concluded that the brain surfaces are insensitive to the substances tested and that the observed effects resulted from movement of the agents into the brain parenchyma.