At present, evidence-based programs (EBPs) to reduce youth violence are failing to translate into widespread community practice, despite their potential for impact on this pervasive public health problem. In this paper we address two types of challenges in the achievement of such impact, drawing upon lessons from the implementation of a partnership model called PROSPER. First, we address five key challenges in the achievement of community-level impact through effective community planning and action: readiness and mobilization of community teams; maintaining EBP implementation quality; sustaining community teams and EBPs; demonstrating community-level impact; and continuous, proactive technical assistance. Second, we consider grand challenges in the large-scale translation of EBPs: (1) building, linking and expanding existing infrastructures to support effective EBP delivery systems, and (2) organizing networks of practitioner-scientist partnerships-networks designed to integrate diffusion of EBPs with research that examines effective strategies to do so. The PROSPER partnership model is an evidence-based delivery system for community-based prevention and has evolved through two decades of NIH-funded research, assisted by land grant universities' Cooperative Extension Systems. Findings and lessons of relevance to each of the challenges are summarized. In this context, we outline how practitioner-scientist partnerships can serve to transform EBP delivery systems, particularly in conjunction with supportive federal policy.