The Youth Risk Behavior Survey (YRBS) Data Summary & Trends Report for 2011–2021 released in February 2023 showed higher rates among female high school students relative to their male peers in endorsements of experiencing poor mental health. This review provides a developmental orientation to promote a biopsychosocial conceptualization of these recent national findings. Young women have higher rates of depressed mood, suicidal ideation, and suicidal plans relative to men, and this gender discrepancy is widening. Higher rates of endorsed school and electronic bullying, social media use, substance use, sexual victimization, and school safety concerns among young women are considered in relation to their sex-specific impact. Recommendations for clinicians are offered to improve the awareness of these important factors and to guide tailored interventions.