The purpose of this study was to determine whether pharmacologic interventions which increase respiratory drive could also reduce flow resistance in the upper airway. Studies were performed in twelve anesthetized supine dogs. In six animals breathing spontaneously through the intact upper airway, intravenous administration of respiratory stimulants (sodium cyanide and nicotine) produced a dose-related decrease in upper airway. In nine animals, upper airway resistance was measured across the isolated upper airway. The stimulants produced a dose-related decrease in upper airway resistance. In both preparations inspiratory resistance fell at lower doses than expiratory resistance. Eventually a dose could be given which resulted in comparable, minimal values of resistance during both inspiration and expiration. Mechanisms for changes in resistance were clarified using lateral radiographs of the neck and transbronchoscopic views of the upper airway. Pharmacologic challenge resulted in a change in the route of airflow (from nose only to nose-and-mouth breathing) as well as a change in caliber of the airway at the level of the naso-pharynx and hyoid apparatus. In anesthetized dogs, respiratory stimulants will decrease upper airway resistance by increasing activation of upper airway muscles which may enlarge the airway, change the route of flow, and thus overcoming collapsing forces produced by increased chest wall muscle activation.