U.S. youths continue to use alcohol, tobacco, and other drugs at alarmingly high rates despite a temporary downward trend in the 1980s. Among an average 500,000 individuals affected annually by substance use, youths (ages 12 to 18) rank as one of the highest groups in morbidity and mortality rates, resulting in many negative consequences. As a result the effectiveness of many prevention strategies has been called into question. This article reviews the extent and social cost of adolescent substance use; standard prevention strategies; prevention under criticism; and salient aspects of successful prevention strategies. Special attention is given to the social influence model of prevention as an effective and amenable model for social work professionals.