AbstractDiseases of the pulmonary vasculature are a cause of increased pulmonary vascular resistance (PVR) in pulmonary embolism, chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary arterial hypertension or decreased PVR in pulmonary arteriovenous malformations on hereditary hemorrhagic telangiectasia, portal hypertension, or cavopulmonary anastomosis. All these conditions are associated with a decrease in both arterial Po2 and Pco2. Gas exchange in pulmonary vascular diseases with increased PVR is characterized by a shift of ventilation and perfusion to high ventilation‐perfusion ratios, a mild to moderate increase in perfusion to low ventilation‐perfusion ratios, and an increased physiologic dead space. Hypoxemia in these patients is essentially explained by altered ventilation‐perfusion matching amplified by a decreased mixed venous Po2 caused by a low cardiac output. Hypocapnia is accounted for by hyperventilation, which is essentially related to an increased chemosensitivity. A cardiac shunt on a patent foramen ovale may be a cause of severe hypoxemia in a proportion of patients with pulmonary hypertension and an increase in right atrial pressure. Gas exchange in pulmonary arteriovenous malformations is characterized by variable degree of pulmonary shunting and/or diffusion‐perfusion imbalance. Hypocapnia is caused by an increased ventilation in relation to an increased pulmonary blood flow with direct peripheral chemoreceptor stimulation by shunted mixed venous blood flow. © 2011 American Physiological Society. Compr Physiol 1:593‐619, 2011.