Highland population (HA) from the Andes, living above 3000 m, have a blunted ventilatory response to increasing hypoxia, breathe less compared to acclimatized newcomers, but more, compared to sea-level natives at sea level. Subjects with chronic mountain sickness (CMS) breathe like sea-level natives and have excessive erythrocytosis (EE). The respiratory stimulation that arises through the peripheral chemoreflex is modestly less in the CMS group when compared with the HA group at the same PETO2. With regard to CO2 sensitivity, CMS subjects seem to have reset their central CO2 chemoreceptors to operate around the sea-level resting PETCO2. Acetazolamide, an acidifying drug that increases the chemosensitivity of regions in the brain stem that contain CO2/H+-sensitive neurons, partially reverses this phenomenon, thus, providing CMS subjects with the possibility to have high CO2 changes, despite small changes in ventilation. However, the same type of adjustments of the breathing pattern established for Andeans has not been found necessarily in Asian humans and/or domestic animals nor in the various high altitude species studied. The differing time frames of exposure to hypoxia among the populations, as well as the reversibility of the different components of the respiratory process at sea level, provide key concepts concerning the importance of time at high altitude in the evolution of an appropriate breathing pattern. © Mary Ann Liebert, Inc.