Although “cor pulmonale” represents a leading cause of death in advanced COPD, there is no clear consensus on its definition. Pulmonary hypertension has been traditionally considered the pathogenetic mechanism leading to right heart dysfunction in COPD, with peripheral oedema usually being attributed to the venous congestion secondary to the increase of right-ventricle filling pressure. The loss in pulmonary capillaries and the vascular remodelling, secondary to chronic hypoxia, cigarette-smoke exposition and systemic inflammation, are well known causes of endothelial dysfunction and pulmonary hypertension in COPD patients. Other mechanisms, such as hypoxic vasoconstriction and alveolar capillary compression in hyperinflated lungs can contribute to the rise of pulmonary arterial pressure during COPD exacerbations, exercise and sleep. In the last decades, however, the role of pulmonary pressure overload in the development of right heart failure has been debated mostly, because of the lack of a clear correlation between pulmonary artery pressure values and the presence of peripheral oedema and/or haemodynamic signs of right heart failure. In addition, the presence of distinct renal and hormonal alterations, suggests that oedema formation in advanced phases of COPD is mostly due to sodium and water retention induced by hypercapnic acidosis and aggravated by severe hypoxemia. Future studies are needed to clarify the possible role of “intermittent hypoxia”, elicited by exercise or sleep, on right heart function and also on sodium and water handling in COPD patients.