Oxygen (O(2)) is essential for aerobic life; however, the level of O(2), whether too low (hypoxia) or too high (hyperoxia), can induce oxidative injury and increase morbidity and mortality. Disruption of O(2) homeostasis represents a major aspect of many disease etiologies and pathobiology. In the past, our laboratory has been using Drosophila melanogaster to investigate the cellular and molecular aspects of the response to hypoxia and oxidative stress. There are several advantages for using Drosophila as a model system, the most important one being an evolutionary conservation of genetic and signaling pathways from Drosophila to mammals. As a proof of this concept, we have shown that we can substantially improve the tolerance of human cells in culture by transfecting these cells with particular Drosophila genes. In this review, we summarize the recent findings from our laboratory using Drosophila as a model system to investigate the genetic basis of hypoxia/hyperoxia tolerance. We have done microarray studies and identified several oxidative stress resistance genes that play an important role in individual paradigms such as constant or intermittent hypoxia, short term (days) or long term (generations) hypoxia/hyperoxia. Our studies provide evidence that a pattern of oxidative stress is specific in inducing a gene expression profile which, in turn, plays an important role in modulating the phenotype. To improve our understanding of oxidative and hypoxic stress as well as its associated diseases, multi-disciplinary approaches are necessary and critical in the study of complicated issues in systems biology.