Photosynthesising cyanobacteria breathed life into what was 1000 million years ago considered a reductive atmosphere, thus providing a selective pressure for the evolution of O2-dependent organisms. However, the fact that molecular O2 exists in air as a free radical renders it a double-edged sword, capable of sustaining life in physiologically controlled amounts, yet fatal when in excess. The controlled delivery and stepwise reduction in PO2 from air to mitochondrion may in itself be considered an evolutionary antioxidant to cope with this biological conundrum. The present review will discuss the potential roles, both good and bad, for free radicals during human adaptation to altered environmental PO2. By combining electron paramagnetic resonance spectroscopy with spin-trapping, we provide direct molecular evidence for increased O2 and carbon-centered radical generation at high-altitude which may seem paradoxical in light of the reduced PO2. Radical-mediated contributions to tissue damage and their subsequent role in the pathogenesis of AMS, HAPE and HACE will also be critically examined. Finally, we focus on the sources, mechanisms and functional significance of free radical generation in hypoxia, with a brief consideration of their more positive role as putative signal transductants, capable of adjusting cellular homeostasis and initiating protective adaptation. Our preliminary studies in humans suggest that radical generation by skeletal muscle is exquisitely sensitive to intracellular PO2 which may provide a unifying theory to explain the "free radical paradox" of high-altitude.