Chronic obstructive pulmonary disease (COPD) is the most prevalent respiratory disease and causes significant morbidity and mortality worldwide. One of the most common complications of the disease is the development of pulmonary hypertension, the presence of which is associated with shorter survival. Classically, arterial hypoxemia has been invoked as the main cause of pulmonary hypertension in this condition. Nevertheless, changes in pulmonary circulation have been identified at initial disease stages, in patients who are not hypoxemic, and in smokers with normal lung function, challenging the concept of hypoxia-driven pulmonary hypertension and providing new insight into their pathogenesis. Recent studies have shown endothelial dysfunction with disregulation of endothelium-derived vasoactive agents, as well as upregulation of growth factors in pulmonary arteries of COPD patients and smokers. Accordingly, endothelial cell damage and dysfunction produced by the effects of cigarette smoke products or inflammatory elements is now considered the primary alteration that initiates the sequence of events resulting in pulmonary hypertension. Furthermore, in COPD vessel remodeling and endothelial dysfunction interfere with the hypoxic vasoconstrictive response of pulmonary arteries, altering the matching between ventilation and perfusion and worsening arterial oxygenation. Cellular and molecular mechanisms involved in these vascular abnormalities are being extensively investigated. Progress in the understanding of the pathobiology of pulmonary hypertension associated with COPD may provide the basis for a new therapeutic approach addressed to correct the imbalance between endothelium-derived vasoactive agents.