The purpose of this guide is to provide analyses and advice that help philanthropists determine where their capital can have the greatest impact in the lives of U.S. disadvantaged students. To meet this objective, three critical questions were addressed: What is a meaningful change to target? What activities lead to that change for at-risk students--and who is producing it? How much does it cost to achieve that change? Academic research, policy briefs, program evaluations, and financial and performance data from nonprofit institutions were reviewed, education scholars and practitioners were interviewed, and site visits to schools and nonprofit educational organizations were conducted. The results were then synthesized to provide a framework for thinking systematically about where high impact opportunities in education exist. This framework identifies the key educational targets necessary for student success as well as leading indicators that help philanthropists understand whether their gifts are achieving the impact they seek. Specific philanthropic on-ramps (i.e., promising practices that the analysis indicates have the potential to make a difference in the lives of disadvantaged students) are outlined and five case examples of organizations that are translating these practices into action are examined. These case examples include back of the envelope, cost-per-impact estimates linking philanthropic dollars with potential results to provide insight into what change realistically costs. The guide concludes with recommendations on selecting organizations to fund, assessing results, and avoiding common pitfalls. This guide provides philanthropists with evidence-based activities to fund, informs their creation of new models without duplicating existing efforts or worse, causing unintended harm, and presents them with the information and structure necessary for testing the value proposition of other models. The following are appended: (1) Examples of philanthropic "on-ramps"; (2) Exemplary models of promising practices mentioned in this report; (3) How we calculated cost per impact in education; (4) About the authors; (5) About the Center for High Impact Philanthropy; (6) References and endnotes; and (7) Advisors and readers. (Contains 2 tables, 1 graph, and 195 references and endnotes.) [This report was produced by the Center for High Impact Philanthropy, School of Social Policy & Practice, University of Pennsylvania.]