Chronic mountain sickness (CMS) is an acquired condition affecting 5%–10% of high-altitude residents. Lifelong exposure to chronic hypoxia triggers excessive erythrocytosis, resulting in an expanded hematocrit. Patients present with symptoms such as dyspnea, fatigue, and palpitations. Complications such as pulmonary hypertension and heart failure are often fatal. Relocation to sea level remains the only definitive management of CMS but poses an unacceptable personal burden. Long-term oxygen therapy provides symptomatic relief, but dependency issues remain a concern. Phlebotomy reduces hematocrit and offers short-term symptom relief. However, side effects and cultural conflicts continue to pose challenges. Acetazolamide, enalapril, and medroxyprogesterone have lowered hematocrit and alleviated symptoms in human trials. Further research into systemic side effects, application in women, and long-term use is required. Methylxanthines, adrenergic blockers, almitrine, and dopamine antagonists showed promise in murine and/or short-term human trials, highlighting the need for further long-term human trials. Inhibition of hypoxia-inducible factor and Janus Kinase-signal transducer and activator of transcription pathways is currently used to suppress hematocrit in polycythemia vera, demonstrating potential application in CMS. Topiramate may stimulate ventilation via acid-base modulation, thus providing therapeutic value. Similarly, the effect of aspirin and caffeine on ventilation may provide a low-cost, accessible intervention.