Despite mentoring's rapidly increasing popularity as an intervention for the prevention of teen alcohol and drug abuse and associated problems, there is little research consensus on its overall effectiveness or on the core principles and components that define effective mentoring. To advance knowledge concerning this important prevention intervention, the Center for Substance Abuse Prevention has designed and funded a multi-site cooperative agreement involving seven mentoring programs. The programs are designed to provide a rigorous outcome evaluation that allows comparisons of differing approaches to organizing and delivering mentoring services to adolescents at high risk for substance abuse. The cooperative agreement guidelines set service parameters and options that focus on issues that are grounded in past research on mentoring prevention interventions. The cooperative agreement includes a quasi-experimental, longitudinal multi-site evaluation that provides evidence-based recommendations to advance the effective use of mentoring as a prevention strategy.