The Keokuk County Rural Health Study (KCRHS) is a population-based, prospective study of health status and environmental exposures of a large stratified random sample of residents in one rural Iowa county. The study focuses on injury and respiratory disease and monitors health care delivery, geriatric health, mental health, and other health outcomes, as well as behavioral risk factors for disease and injury. Injury and disease prevalence is investigated in relation to occupational, agricultural, and other environmental exposures. The KCRHS enrolled 1004 families in Round 1 (1994 to 1998) and 1002 families in Round 2 (1999 to 2004). Participants range in age from newborn to 98 years of age and are about equally divided between males and females. The families live in farm, rural nonfarm, and town households, representing men, women, and children, the elderly, farmers, and nonfarmers. The KCRHS is currently in Round 3 (2006-2011). Although the sample is stratified by residence type, the entire county is, by definition, rural, because the largest town has fewer than 2500 residents. Using the Keokuk County Rural Health Study as an example, this paper describes the methodological challenges faced in conducting a large rural prospective population-based cohort study. Some of these challenges are inherent in any large cohort study; others are unique to rural cohort studies. Topics considered include planning the study, developing the protocol, sampling, recruiting and tracking subjects, data collection and management, sustaining funding, relating to the community, and sharing data.