The mental, emotional and behavioral health problems of high-risk youth and youth living in high-risk communities are not inevitable and can be prevented. A shift from the nation’s focus on treating disease and illness after it occurs to a concentrated effort on preventing the root causes of these problems is needed. Prevention science suggests a comprehensive multitiered approach that provides evidence-based prevention supports for children and youth at each developmental stage and across multiple social contexts is likely to result in the greatest health impact and return on investment. However, actually implementing this approach at a neighborhood level has remained a challenge and an ongoing research gap especially in high-risk communities. This article describes a process and provides a case study example for implementing a comprehensive, multitiered approach in a high-risk community. This includes assessing and prioritizing the specific needs of individuals and communities; selecting evidence-based programs based upon assessed needs; and creating a continuum of programs to improve the health and well-being of youth across developmental age spans, social contexts, and levels of risk. Operational details and challenges for organizing and implementing this comprehensive approach are also described. We estimate that the collective impact of a multitiered evidence-based approach, implemented with fidelity, could conservatively result in a 30 to 40% reduction in problem behaviors.