Oxygen plays a pivotal role in the metabolism and activities of mammals. However, oxygen is restricted in some environments-subterranean burrow systems or habitats at high altitude or deep in the ocean-and this could exert hypoxic stresses such as oxidative damage on organisms living in these environments. In order to cope with these stresses, organisms have evolved specific strategies to adapt to hypoxia, including changes in physiology, gene expression regulation, and genetic mutations. Here, we review how mammals have adapted to the three high-altitude plateaus of the world, the limited oxygen dissolved in deep water habitats, and underground tunnels, with the aim of better understanding the adaptation of mammals to hypoxia.