Background: The Physical Activity Research Center developed a research agenda that addresses youth physical activity (PA) and healthy weight, and aligns with the Robert Wood Johnson Foundation’s Culture of Health. This paper summarizes prioritized research studies with a focus on youth at higher risk for inactive lifestyles and childhood obesity in urban and rural communities. Methods: Systematic literature reviews, a survey, and discussions with practitioners and researchers provided guidance on research questions to build evidence and inform effective strategies to promote healthy weight and PA in youth across race, cultural, and economic groups. Results: The research team developed a matrix of potential research questions, identified priority questions, and designed targeted studies to address some of the priority questions and inform advocacy efforts. The studies selected examine strategies advocating for activity-friendly communities, Play Streets, park use, and PA of youth in the summer. A broader set of research priorities for youth PA is proposed. Conclusion: Establishing the Physical Activity Research Center research agenda identified important initial and future research studies to promote and ensure healthy weight and healthy levels of PA for at-risk youth. Results will be disseminated with the goal of promoting equitable access to PA for youth.