The National Institutes of Health convened a workshop to engage researchers and practitioners in dialogue on research issues viewed as either unique or of particular relevance to rural areas, key content areas needed to inform policy and practice in rural settings, and ways rural contexts may influence study design, implementation, assessment of outcomes, and dissemination. Our purpose was to develop a research agenda to address the disproportionate burden of cardiovascular disease (CVD) and related risk factors among populations living in rural areas. Complementary presentations used theoretical and methodological principles to describe research and practice examples from rural settings. Participants created a comprehensive CVD research agenda that identified themes and challenges, and provided 21 recommendations to guide research, practice, and programs in rural areas.