At high altitude, hypoxia is the fundamental challenge that sojourners and native residents face, necessitating physiological acclimatization and/or genetic adaptation to overcome. Long-resident populations of high altitude, such as Himalayans and Andeans, have adapted to hypoxia through genetic changes that impact altitude-adaptive phenotypes. High-altitude sojourners display epigenetic changes that may facilitate plastic physiological responses to low oxygen availability. Ongoing research is working towards identifying the functional consequence of altitude-adaptive variation, both genetic and epigenetic. Together, these results provide key insights into the patterns of genetic adaptation and epigenetic plasticity to high-altitude hypoxia, shed light on genetic variation contributing to complex phenotypes, and are of potential importance for public health given HIF-pathway involvement with various disease processes such as chronic ischemic disease and regulation of tumor growth. Free, open to the campus and community. Presented with the support of the CU Museum.