Abstract People living in poor rural communities in the South live shorter and less healthy lives than those residing elsewhere in the United States. The basis of this very high rural burden of heart, lung and blood diseases (HLBS), which does not spare any race, is unclear. Within the same Southern regions, however, there are counties with very low risk of disease that have profiles of poverty, race/ethnicity, and rurality similar to the high risk ones. Therefore, we do not understand which factors amplify risk in the rural South, and what renders some communities resilient but others more vulnerable. To study this problem, we will recruit a RURAL (Risk Underlying Rural Areas Longitudinal Study) cohort of 4000 participants (age 35-64 years, 50% women; 44% whites, 45% blacks, 10% Hispanic) from ten of the poorest rural counties in four Southern states (Kentucky, Alabama, Mississippi and Louisiana). We will target six higher risk and four lower risk rural counties `paired within state' for their degree of poverty, race/ethnic composition, and their total population sizes. Using a self-contained mobile examination unit (with a CT scanner and digital technology), we will conduct an examination to: characterize the local built, social and economic environments; assess familial, lifestyle factors, and medical history; assay standard and novel HLBS risk factors, including genetic risk; evaluate lung function; measure subclinical disease burden (CT scan for coronary calcium and lung disease; ankle-brachial index; pulse wave velocity); test physiological responses to postural change, handgrip, a 6-minute walk, and an oral glucose load; appraise the utility of mHealth tools in rural settings with `take-home' smartphones and wearable activity monitors; build bio- and data-repositories, and robust community collaboratives for current and future studies. Surveillance of participants will help us to identify and adjudicate/validate new HLBS disease events. Our central hypothesis is that differences in the HLBS risk among people living in these 10 high- and low-risk rural Southern counties arise from the synergistic interaction among diverse exposures. An adverse exposome creates greater `wear and tear' of the body, affects psychosocial well-being, and impacts lifestyle choices that influence HLBS risk. Increased genetic predisposition, greater poverty, and minority status all exacerbate risk. We will test this hypothesis with the following aims: Aim 1. Characterize the exposome comprehensively at the individual and at the community-level in RURAL participants, and relate it to biological function and HLBS risk cross-sectionally; study how these associations may be modified by age, sex, race/ethnicity, and residence in a high vs. low-risk county. Aim 2. Relate the exposome to the incidence of HLBS disease prospectively, and evaluate effect modification by age, sex, race/ethnicity, and residence in a high vs. low-risk AMD county. We will analyze the collected data and publish our results, and share major findings with these rural communities. RURAL will inform us about what causes the burden of HLBS disease in the rural South and how to alleviate it.