There have been extensive studies and experiments on cells, tissues and animals that are susceptible to low O2, and many pathways have been discovered that can lead to injury in mammalian tissues. But other pathways that can help in the survival of low O2 have also been discovered in these same tissues. It should be noted, however, that the mechanisms that can lead to better survival in susceptible mammalian tissues have quantitatively a 'narrow range' for recovery, since these tissues are inherently at risk. Another strategy for understanding the susceptibility of organisms is to learn about pathways used by anoxia-resistant animals. Approximately a decade ago, I and my co-workers discovered that one such animal, Drosophila melanogaster, is very tolerant of low O2. Here, I detail some of the studies that we performed and the strategies that we developed to understand the mechanisms that underlie the fascinating resistance of Drosophila to measured partial pressure of O2 of zero. We employed three ideas to try to address our questions: (1) mutagenesis screens to identify loss-of-function mutants; (2) microarrays on adapted versus naïve flies; and (3) studying cell biology and physiology of genes that seem important in flies and mammals. The hope is to learn from these studies about the fundamental basis of tolerance to the lack of O2, and with this knowledge be able to develop better therapies for the future.