The relationship between altitude and the development of paragangliomas (PGLs), rare tumors within the sympathetic nervous system has been suggested since the early 1970's. Here, we discuss how altitude, marked by lower barometric pressure and hypoxia (reduced oxygen partial pressure), may influence cancer rates. Chronic hypoxia triggers physiological changes, such as carotid body (CB) hyperplasia and a higher incidence of head and neck paragangliomas (HN-PGL) which has been reported in high-altitude populations, with a predominance of females among affected individuals. The involvement of hypoxia signalling in PGL tumorigenesis is further reinforced by the demonstration that genetic mutations, (particularly in VHL, SDHx and EPAS1 genes) cause a pseudo-hypoxic response. Furthermore, somatic mutations in EPAS1 are also linked to an increased risk of PGL in individuals with chronic hypoxemic conditions such as cyanotic congenital heart disease or haemoglobin diseases. Altogether, this review emphasizes the unique sensitivity of paragangliomas to hypoxic signalling, and shows that whether due to low environmental oxygen at high altitudes, diseases, or genetic mutations, hypoxia plays a pivotal role in PGL formation.