From the Center for Substance Abuse Prevention, this document comprises a series of monographs from the series “Points of Prevention.” Discussing major findings of the National Cross-Site Evaluation of High Risk Youth Programs, this report includes an overview of the National High-Risk Youth Demonstration Grant Program and details findings in a series of four monographs. The overview presents various statistics demonstrating that High-Risk Youth (HRY) substance abuse prevention programs significantly reduce and prevent rates of substance abuse, and details the basic design of the HRY program itself. This study focused on over 10,500 at-risk youths from 48 sites, over a 5-year time period. Discussing the ways that gender, family, peers, school, community, and society all influenced youth substance abuse, this report details the methodology and study design that enabled the comprehensive cross-site evaluation of substance abuse programs. The first monograph presents the central aims of the evaluation project, contending that HRY programs significantly reduce and prevent substance abuse, and that gender, family, peers, school, community, and society all influence youth substance abuse. Through the use of graphs and charts, this report elaborates each of the study’s major findings, concluding that alcohol, tobacco, and marijuana use are prevented and reduced in HRY’s by science-based, community oriented, substance abuse programs. The second monograph focuses on the web of influence affecting HRY’s. This section describes the characteristics of the youths sampled in the 5-year study, detailing external and internal risks contributing to youth substance abuse, external and internal youth protection against substance abuse, and the power of social norms concerning substance use and abuse, finding that schools, families, communities, and peer association all comprise the web of influence which leads some individuals to engage in substance use and abuse. The third monograph describes various measurements used to determine program effectiveness, elaborating on substance abuse programs’ characteristics, effects, setting, and implementation. This section presents findings on substance abuse program content, delivery method, coherence, contact with youth, and service settings. The fourth monograph discusses the issues of substance use and abuse, risk, protection, and gender, suggesting gender differences in substance use and prevention and in responses to substance abuse prevention programs.