In this perspective, we review published data which support the concept that many or most chronic and progressive lung diseases also involve the lung vessels and that microvascular abnormalities and endothelial cell death contribute to the pathobiology of emphysema. Lung vessel maintenance depends on Vascular Endothelial Growth Factor signaling and both are compromised in the emphysematous lung tissue. Although hypoxic pulmonary vasoconstriction has been considered as an important factor contributing to the vascular remodeling in chronic obstructive pulmonary disease (COPD) (COPD/emphysema, it is now clear that inhaled cigarette smoke can damage the lung vessels independent of the lung vascular tone. We propose that a “sick lung circulation” rather than the right heart afterload may better explain the cardiac abnormalities in COPD patients which are usually summarized with the term “cor pulmonale.” The mechanisms and causes of pulmonary hypertension are likely complex and include vessel loss, in situ thrombosis, and endothelial cell dysfunction. Assessment of the functional importance of pulmonary hypertension in COPD requires hemodynamic measurements during exercise.