The effects of ventilatory hypoxia and hypercapnia and perfusion hypoxia and hypercapnia on pulmonary vascular resistance were studied in the intact lamb using right heart techniques to isolate and perfuse the left lower lobe. Ventilatory hypoxia increased vascular resistance in the left lower lobe by constricting predominantly vessels upstream from small lobar veins, presumably small arteries. The response to hypoxia was not blocked by phentolamine and diphenhydramine in doses that markedly decreased pressor responses to norepinephrine and histamine in the lung. Perfusion hypoxia did not alter vascular resistance in the perfused lobe. Ventilatory hypercapnia increased vascular resistance in the lung by constricting mainly upstream vessels, whereas perfusion hypercapnia decreased resistance by dilating upstream vessels. These data indicate that histamine and catecholamines are not involved in the response to alveolar hypoxia. These results suggest that the sensor site for ventilatory hypoxia is close to the alveolus since the response is unrelated to lobar arterial Po2. It is concluded that systemic reflexes are not necessarily involved in the response of the pulmonary vascular bed to ventilatory hypoxia or hypercapnia and that the magnitude and rapidity of this response suggest that it may represent an important local mechanism for the control of ventilation-perfusion relationships in this species.