All mammals and birds must develop effective strategies to cope with reduced oxygen availability. These animals achieve tolerance to acute and chronic hypoxia by (a) reductions in metabolism, (b) the prevention of cellular injury, and (c) the maintenance of functional integrity. Failure to meet any one of these tasks is detrimental. Birds and mammals accomplish this triple task through a highly coordinated, systems-level reconfiguration involving the partial shutdown of some but not all organs. This reconfiguration is achieved through a similarly complex reconfiguration at the cellular and molecular levels. Reconfiguration at these various levels depends on numerous factors that include the environment, the degree of hypoxic stress, and developmental, behavioral, and ecological conditions. Although common molecular strategies exist, the cellular and molecular changes in any given cell are very diverse. Some cells remain metabolically active, whereas others shut down or rely on anaerobic metabolism. This cellular shutdown is temporarily regulated, and during hypoxic exposure, active cellular networks must continue to control vital functions. The challenge for future research is to explore the cellular mechanisms and conditions that transform an organ or a cellular network into a hypometabolic state, without loss of functional integrity. Much can be learned in this respect from nature: Diving, burrowing, and hibernating animals living in diverse environments are masters of adaptation and can teach us how to deal with hypoxia, an issue of great clinical significance.