Various rural prevention research challenges have been articulated through a series of sessions convened since the mid 1990s by the National Institutes of Health, particularly the National Institute on Drug Abuse. Salient in this articulation was the need for effective collaboration among rural practitioners and scientists, with special consideration of accommodating the diversity of rural areas and surmounting barriers to implementation of evidence-based interventions. This paper summarizes the range of challenges in rural prevention research and describes an evolving community-university partnership model addressing them. The model entails involvement of public school staff and other rural community stakeholders, linked with scientists by Land Grant University-based Extension system staff. Examples of findings from over 16 years of partnership-based intervention research projects include those on engagement of rural residents, quality implementation of evidence-based interventions, and long-term community-level outcomes, as well as factors in effectiveness of the partnerships. Findings suggest a future focus on building capacity for practitioner-scientist collaboration and developing a network for more widespread implementation of the partnership model in a manner informed by lessons learned from partnership-based research to date.