Aspergillus fumigatus is a ubiquitous mold found in soil and organic debris that is currently the most frequent cause of airborne invasive fungal infections in immunocompromised individuals. In this study the hypothesis that hypoxia is a stress faced in vivo by A. fumigatus and that the ability to sense, adapt to, and grow in hypoxic conditions is a virulence attribute of this human fungal pathogen was tested. Utilizing specific staining in 3 clinically relevant murine models, it was shown for the first time that hypoxic microenvironments occur at sites of A. fumigatus infection arguing that, A. fumigatus has to be able to adapt to these oxygen-limited conditions in order to cause disease. In this context, a SREBP ortholog was identified and characterized. Importantly, the SREBP null mutant was unable to grow in hypoxia and virtually avirulent. Interestingly, oxygen sensing and hypoxia adaptation mechanisms can be identified in other fungi suggesting an important role for these mechanisms for fungal biology and virulence. In addition, it was found that A. fumigatus utilizes ethanol (EtOH) fermentation in vivo and that this pathway is induced in in vitro hypoxia. While fermentation was shown to not be essential for growth in hypoxia and fungal virulence, it was found that loss of the alcohol dehydrogenase involved in EtOH fermentation under hypoxic conditions resulted in significant changes in the host immune response. Lastly, it was found that the mitochondrial electron transport chain (ETC) of A. fumigatus seems to be involved in hypoxic signaling as a deletion of cytochrome C resulted in loss of EtOH fermentation activation in hypoxia. Furthermore, the ETC plays a role in the oxidative stress response and is important for A. fumigatus pathogenesis. Overall, the presented data shows that hypoxia occurs at the site of A. fumigatus infection and it suggests an important previously unidentified link between hypoxia adaptation and fungal pathogenesis of A. fumigatus.