This report discusses successful approaches to conducting health literacy-directed studies with community clinics and agencies in rural areas of Louisiana. Some lessons learned from two studies in isolated rural areas with a history of health, educational, and economic disparities are presented. The first is a qualitative study eliciting patients’, providers’ and community members’ understanding, access and acceptance of clincial trials. The second is an overview of health literacy interventions that build on each other to improve annual colorectal cancer screening in rural commuity clinics. The results suggest rural providers and patients are interested in participating in clinical trials. To increase participation in clinical trials in rural areas, academic researchers need to develop ongoing “bi-directional” working relationships with rural clinics and agencies. The support of primary care providers trusted by patients is essential. Plain language and culturally appropriate patient education material developed with the input of patients and providers and on-going telephone outreach are effective in increasing initial colon cancer screening among low-income rural patients. More intensive strategies are needed to sustain annual screening. Implementation of health literacy research strategies may help address barriers to understanding and access to appropriate studies and preventive health services.