Recent research has highlighted the significant contribution families make in the prevention of HIV risk behaviors among adolescents. As the most proximal and fundamental social system influencing child development, families provide many of the factors that protect adolescents from engaging in sexual risk behaviors. Among these are positive family relations, effective communication about sexuality and safer sexual behaviors, enhancement and support of academic functioning, and monitoring of peer activities. HIV risk behaviors occur in a social context, and it is becoming clear that the earliest and most effective way to intervene is in the context where one initially learns about relationships and behavior--the family. Both the Centers for Disease Control and Prevention and the National Institute for Mental Health have taken steps to support and emphasize research that will further elucidate our understanding of the role of families in HIV prevention. This article uses Ecodevelopmental Theory to guide and organize the findings of this promising research area. Within this context, and with special attention to the comorbidity of adolescent problem behaviors, this article reviews empirical research on the role of families in HIV prevention, discusses current intervention efforts that involve families and ecosystems, and addresses prospects and implications for future research and interventions.