Chronic cor pulmonale involves the enlargement of the right ventricle as a result of pulmonary hypertension due to pulmonary disorders involving the lung parenchyma, bellows function, or ventilatory drive. The right ventricular hypertrophy that occurs in chronic cor pulmonale is a direct result of chronic hypoxic pulmonary vasoconstriction and subsequent pulmonary artery hypertension, leading to increased right ventricular work and stress. We discuss methods by which hypoxic vasoconstriction and reduction in the pulmonary vascular bed lead to the development of pulmonary artery hypertension. This article reviews the interaction of the pulmonary vasculature and right ventricle in the non-diseased state as well as during disease exacerbations. Ventricular dependence and its contribution to the pathophysiology of right ventricular failure are also reviewed. In addition, we provide an overview of specific disease states that can result in the development of chronic cor pulmonale including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep apnea, alveolar hypoventilation disorders, and primary pulmonary hypertension. We also review the current diagnostic studies used to evaluate and study cor pulmonale.