Over the past few years, there has been significant growth in the number of multi-site, cross-sector initiatives to improve communities and the lives of their residents. Through a comprehensive literature review, interviews with key project evaluators and funders, a recap of a December 2014 roundtable discussion, and the authors’ significant expertise, this report provides detailed descriptions of “what works” and “pitfalls” in its analysis of design elements and project parameters of both past and current multisite initiatives. In addition, the paper provides insights into the design and implementation of place-based efforts for community development practitioners, financial institutions, and other organizations, such as healthcare payers, who are involved in site-specific initiatives seeking to improve the economic well-being of low-income residents.