This article reports on the lessons learned from a five-year, evidence-based substance abuse prevention initiative conducted in three school districts. Traditional outcome measures yielded no significant program effects, despite the use of an evidence-based curriculum. The failure to find significant statistical results is discussed in terms of four issues that are crucial for successful program implementation: (1) initial selection of an appropriate program, (2) adequate stakeholder involvement and school readiness, (3) attention to program fidelity, and (4) evaluation planning. Based on the literature and the authors' experience, practice implications are offered to maximize the effectiveness of school-based prevention programs.