The development of secondary pulmonary hypertension (PH) as a result of pulmonary disease, both in adults and children, considerably worsens prognosis. Chronic hypoxia appears to be the cause, as long-term oxygen therapy (LTOT) reverses or at least impedes the progressive development of PH. There is now clear evidence that acute hypoxia causes smooth muscle contraction in pulmonary arteries through a direct effect on intracellular calcium levels. Subsequent relaxation depends upon activation of ion transport mechanisms which can be modified by circulating hormones such as the naturally occurring ouabain. Sustained hypoxia can cause adaptation of pulmonary endothelium. One change is a reduction in nitric oxide (NO) production, possibly through reduced activity of the formative enzyme nitric oxide synthase. Basal production of NO appears important in many species including man in determining the low pulmonary vascular resistance. Impaired endothelial NO production as a result of sustained hypoxia may well enhance the development of secondary PH. Much attention is now focused on the regulation of nitric oxide synthase, both the constitutive form in endothelium as well as the inducible form of inflammatory cells. It is possible that either gene transcription or translation are modified when endothelial cells are exposed to chronic hypoxia. This allows the opportunity for therapeutic intervention. More needs to be learnt about the cellular and molecular adaptation to hypoxia in man but novel approaches to treatment may soon arrive for patients with chronic obstructive lung disease and secondary pulmonary hypertension.