In a hypoxic environment, HIF-2α is stabilized, which moves to the nucleus and activates the transcription of the erythropoietin (EPO) gene. Increased EPO supports the formation of red blood cells in the bone marrow, thereby increasing hemoglobin (Hb) levels and improving oxygen transport. The HIF-2α-EPO-Hb axis controls physiological responses, such as adaptation to high altitude, as well as pathological conditions. Disruption of this axis causes anemia in chronic kidney disease, excessive activation leads to high-altitude polycythemia and tumor progression, including kidney cancer. The complex regulatory networks of the axis in tissues and in diseases are not fully understood. Targeted drugs, such as HIF prolyl hydroxylase inhibitors and HIF-2α inhibitors, face problems with tissue selectivity, long-term safety, and prediction of efficacy. The review evaluates molecular mechanisms, dysregulation in chronic hypoxic diseases and tumorigenesis, as well as advances in therapies. Discusses theoretical foundations for future research and clinical interventions.