This article describes the development of a mass media smoking prevention intervention targeted primarily toward adolescent girls at increased risk for smoking and assesses its outcomes. A cohort of 5,458 students was surveyed at baseline in Grades 4-6 and annually for 4 years. Through diagnostic and formative research, media messages were created to appeal especially to girls. Students beginning in Grades 5-7 received the 4-year media intervention and a school program in two communities, while students in two matched communities received the school program alone. Media targeting techniques resulted in high levels of message appeal and exposure consistent with effects on mediating variables and 40% lower weekly smoking at Grades 8-10 for girls receiving the media and school interventions compared to school alone. Smoking behavior effects were maintained at Grades 10-12. These results indicate that mass media interventions targeting specific audience segments can reduce substance use behavior for those segments.