Considerable progress has been made in prevention science, and since reaching a high in the late 1970s and early 1980s, overall substance use has declined in the United States. However, for some populations and substances, smaller declines or even increased use has been observed. Notably, the traditional gender gap in substance use has decreased substantially, and it has disappeared completely for some substances, especially among younger cohorts. This article was written to integrate existing evidence on the relevance of gender for substance use prevention research and to move the field forward by suggesting theoretical models that might inform future prevention research with girls. This article reviews the following: (a) trends in substance use, (b) gender differences in risk factors, and (c) theoretical models deemed relevant to substance use prevention among girls. Finally, recommendations regarding needed research and prevention strategies that take gender, race, and ethnicity into account are provided.