<p>High altitude exposes humans to hypobaric hypoxia and poses a significant challenge for human performance and survival. Humans have adapted to the chronic hypoixa of high altitude in several geographical locations and nevertheless, the fundamental questions regarding the functional links between those adoptive unique phenotypic attributes and the associated cellular and molecular signaling mechanisms remains unanswered. The high-altitude acclimatization and adaptation responses are primarily orchestrated by hypoxia inducible factor (HIF). However, some HIF-independent response pathways exists and act either in coordination and/or in parallel to HIF to mediate the physiological response of hypoxia. Recently, several multi-omic analysis studies demonstrated crucial oxygen homeostatic and metabolic signaling pathways in hypoxia including members of nuclear receptor (NR’s) superfamily like LXR’s, RXR’s, ER’s and PPARA’s. Since acclimatization and adaptation to high altitude confers several benefits for the prevention of various high altitude illnesses, the cellular and molecular signaling mechanisms underlying oxygen homeostasis during acute and prolonged high altitude exposure becomes an attractive avenue for understanding the physiology of adaptation and pathophysiology of mal-adaptation. Members of NR’s are of particular interest owing to their involvement in multiple physiological functions and their possible role in epigenetic regulation due to the presence of well defined DNA and ligand binding domains. In this review, we summarize the current understanding of the involvement of NR’s in regulation of physiological responses hypoxia and how they may contribute for high altitude adaptation. Additionally, we have made an effort to draw attention to the connection between NRs and EVs.</p> Graphical Abstract <p></p>