Recently identified as the top concern of teens, mental health issues now compete with sexual health risks as major threats to the well-being of adolescent females. Depression and anxiety can lead to or compound the negative repercussions of sexual behavior choices that result in disproportionately high rates of sexually-transmitted infections (STIs), hetero-sexually acquired HIV, and unplanned pregnancy rates in girls ages 15-19. There are a limited number of CDC- and DHHS-recognized HIV/STI and teen pregnancy evidence-based interventions (EBIs) targeted to adolescent girls of diverse races/ethnicities and none that simultaneously address common mental health disorders. The Health Improvement Project for Teens (HIPTeens), a manualized gender-specific sexual risk reduction intervention, and the Creating Opportunities for Personal Empowerment (COPE) Program, a manualized cognitive-behavioral skills intervention that reduces depression and anxiety, are recognized by national agencies as strong EBIs that have successfully improved their targeted outcomes. Baseline data from the HIPTeens clinical trial revealed that a substantial portion of the more than 700 girls enrolled had moderate to high levels of depressive symptoms as well as other mental health challenges (e.g., binge drinking and eating, cannabis use). Thus, there is an urgent need to combine EBIs, such as HIPTeens and COPE, to curtail these leading public health problems confronting today's adolescents.