Many populations in rural settings may suffer disproportionate environmental health burdens, such as from air pollution or extreme temperatures. Yet the vast majority of research on environmental health disparities for air pollution, as well as research on air pollution and health more generally, is conducted for cities. The people, communities, and air pollution sources and mixtures are quite distinct in rural versus urban settings, such that strategies may not be sufficiently protective of health for rural populations. Similarly, research on the health consequences of high and low temperatures, especially for prolonged periods of heat (i.e., “heat waves”), has almost exclusively focused on urban areas. Therefore, current research has major scientific gaps on how the health of rural populations, including for subpopulation groups, is impacted by air pollution and extreme temperature. The rural south, particularly the Appalachian region, has higher rates of adverse health outcomes in both older populations (>65y) and infants, compared to national averages. Within the south, rural populations suffer higher rates of multiple morbidities than urban populations, including health outcomes that are linked to air pollution and extreme heat and cold in urban environments. Rural residents also have lower overall income, lower educational attainment, less access to health care, and three years lower life expectancy than their urban counterparts. Evidence suggest that some health disparities are larger for rural subpopulations than their urban counterparts. Given the differences in populations, behaviors, environmental hazards, and socioeconomic status (SES), the associations between air pollution, extreme temperature, and health could differ substantially for rural and urban settings. These relationships may also differ across types of rural areas, given the heterogeneity of rural environments. Scientific evidence is urgently needed on the disproportionate impacts of air poll