More than 140 million people live above 2,500 m worldwide, about 80 million in Asia, and approximately 35 million in the Andean mountains. The greatest population density is located above 3,500 m. Chronic mountain sickness (CMS) is one of the most important high-altitude pathologies in the majority of mountainous regions of the world. Its hallmark sign is excessive erythrocytosis (EE). In more advanced and severe stages, high-altitude pulmonary hypertension (HAPH) appears frequently, with related remodeling of pulmonary arterioles and right ventricular hypertrophy. This chapter summarizes CMS clinical features, physiology, pathology, pathogenesis, epidemiology, and genetics. It is based on a systematic review of worldwide literature, with emphasis in the Andes, including the literature from pioneering work conducted several decades ago. The role of the evolution of erythrocytosis and of ventilatory function in the development of hypoxemia is highlighted. Hematologic and pulmonary systems are affected by several risk factors including age, obesity, sleep disorders, menopause, air, and metal pollution, and therefore, these aspects are analyzed as the basis of secondary CMS. We also examine how hypoxia and/or EE affect plasma volume, pulmonary hemodynamics, autonomic nervous system, kidneys, and endocrine function. A section on prevention and treatment discusses different available treatments and future therapeutic and prevention prospects.