Interventions that promote sexual health communication between adolescents and their parents or other primary caregivers are an important tool for reducing female adolescents’ behavioral risk. Understanding the mechanisms by which interventions effectively foster communication can inform future programs. Using mixed methods data from an evaluation of Let’s Talk, this analysis explores the role of parental knowledge, the quality of the parent-adolescent relationship, and the mental health of both parties on caregiver-adolescent sexual health communication. Findings suggest that a holistic intervention approach emphasizing caregiver-adolescent relationship development and designed to support the mental health of both parties may hold significant promise for enhancing sexual health communication.