This article leads off the special issue’s first section on Health, Mental Health, and Well-Being Today Among Marginalized Populations. It draws from multiple disciplines to address COVID-19 vaccine hesitancy in rural areas of the United States. Presenting a synthesis of literature on rural vaccine hesitancy and emerging research and scientific opinion on COVID 19, we identify likely factors in rural decision-making about COVID-19 vaccination. Vaccination is underway, with plans to provide access to every U.S. resident. However, polls suggest vaccine hesitancy may compromise our ability to reach the goal of herd immunity, and rural residents express more hesitancy than their urban and suburban counterparts. Drawing on Thomson et al.’s (2016) identification of five dimensions of vaccine uptake, we use a social-ecological approach to propose actions to increase vaccine acceptance on individual, interpersonal, organizational, community, and cultural levels. This conceptual paper is a starting point for rural health and human services administrators and practitioners seeking to reduce COVID-19 vaccine hesitancy in their communities in this early stage of COVID-19 vaccination.