The purpose of this initiative is to support research to improve health and promote health equity in rural populations. Rural populations experience high rates of many causes of morbidity and disability, and high and increasing rates of premature death. Meaningful and sustained improvements in the health of rural populations require effective solutions to address the underlying causes. Applications responding to this Notice of Funding Opportunity (NOFO) should develop, adapt, or implement intervention strategies addressing social determinants of health (SDOH) to improve health and promote health equity in rural populations. This funding opportunity encourages studies that use a wide range of methodological approaches that enhance access to, and acceptability and effectiveness of, interventions in rural populations, such as community-engaged research approaches that build on the strengths of rural communities.