Evidence-based preventive interventions developed over the past two decades represent great potential for enhancing public health and well-being. Research confirming the limited extent to which these interventions have been broadly and effectively implemented, however, indicates much progress is needed to achieve population-level impact. In part, progress requires Type 2 translation research that investigates the complex processes and systems through which evidence-based interventions are adopted, implemented, and sustained on a large scale, with a strong orientation toward devising empirically-driven strategies for increasing their population impact. In this article, we address two core challenges to the advancement of T2 translation research: (1) building infrastructure and capacity to support systems-oriented scaling up of evidence-based interventions, with well-integrated practice-oriented T2 research, and (2) developing an agenda and improving research methods for advancing T2 translation science. We also summarize a heuristic "Translation Science to Population Impact (TSci Impact) Framework." It articulates key considerations in addressing the core challenges, with three components that represent: (1) four phases of translation functions to be investigated (pre-adoption, adoption, implementation, and sustainability); (2) the multiple contexts in which translation occurs, ranging from community to national levels; and (3) necessary practice and research infrastructure supports. Discussion of the framework addresses the critical roles of practitioner-scientist partnerships and networks, governmental agencies and policies at all levels, plus financing partnerships and structures, all required for both infrastructure development and advances in the science. The article concludes with two sets of recommended action steps that could provide impetus for advancing the next generation of T2 translation science and, in turn, potentially enhance the health and well-being of subsequent generations of youth and families.