Our data also provide physiological evidence for the critical role of oxidative stress in increasing genomic instability, an essential driver in the multi-step process of tumorigenesis. Most importantly, our study provides proof of concept that it is possible to alter the time course of tumor development by the simple modulation of ambient oxygen, the essential factor for oxidative stress. We have previously shown that increased intracellular oxygen levels caused by the disruption of mitochondrial function may contribute to increased ROS generation and genomic DNA damage. Thus, the current in vivo data support the in vitro observation that oxygen consumption via mitochondrial respiration may serve a fundamentally important function to guard against oxygen-associated genotoxicity. A previous study has reported that the antioxidant N-acetyl cysteine can delay Iloprost tumorigenesis in p53-deficient mice, underscoring the importance of p53��s antioxidant activities in tumor suppression. Our study provides important complementary data to validate this prior observation which used a pharmacologic agent. Furthermore, the current study is unique in that through a physiological manipulation, we have demonstrated the importance of oxygen in modulating genomic instability. Although our results show that lowering oxygen reduces genomic instability and tumorigenesis in vivo, hypoxic conditions in various systems have also been shown to promote tumor cell growth through HIF1-a induction. Conversely, established cancer cells engineered to over-express myoglobin, thus containing higher intracellular oxygen and lower HIF1-a levels, exhibit a decrease in xenograft tumor growth. However, in our experiments tissues obtained from mice exposed to 10% oxygen did not show a Thapsigargin significant increase in HIF1-a activity at this level of physiologically adaptable hypoxia. Thus, our observations are more likely to stem from a delay in tumor initiation due to reduced genomic instability in low oxygen rather than reflect the growth activities known to be stimulated by HIF1- a in established tumor cells. Supraphysiologic levels of oxygen, including hyperbaric conditions, have been shown to inhibit tumorigenesis. However, oxidative stress responses such as p53 stabilization may contribute to inhibiting tumor growth. As demonstrated by many elegant studies, ROS plays multiple roles depending on various factors.