Prevention researchers and school personnel lack a common understanding concerning the opportunities and burdens of school-based drug prevention research. In this article, we review issues related to researching substance abuse prevention programs in school settings, and assess challenges related to recruitment, communication, research design, surveying, and ensuring program fidelity. We conclude that before any school is enrolled, there must be a mutual understanding as to the nature and extent of the study's requirements and what adjustments a school will have to make to support a successful collaboration. Further, researchers must understand that schools' responsibilities for preparing students to perform well on academic and standardized tests will always overshadow the value they place on participating in studies to evaluate the effectiveness of prevention curricula.