Problematic substance use complicates treatment for youth and families who have been impacted by trafficking and commercial sexual exploitation (T/CSE). Youth with problematic substance use face additional threats to safety and barriers to treatment. Because the mental health and substance use treatment fields have historically been siloed, there is a lack of therapeutic guidance for treatment providers working with youth with these intersecting challenges. This panel discussion will explore the complex relationship between substance use and T/CSE. Panelists will discuss challenges commonly encountered when working with youth with problematic substance use who have experienced T/CSE, inviting participants to share about their own work. Panelists will highlight lessons learned through the work of several national anti-trafficking programs, including My Life My Choice, the National Center on Child Trafficking (NCCT), and Project REACH. The panel will share essential guidance for mental health and substance use treatment providers when working with youth and families who have been impacted by T/CSE and substance use. Panelists will discuss the NCCT’s development of treatment guidelines for exploited youth who struggle with problematic substance use. The substance use treatment guidelines are a companion to the NCCT’s Consensus Mental Health Treatment Guidelines for youth impacted by T/CSE. The substance use guidelines are grounded in the perspectives of youth and adults with lived experience of T/CSE and problematic substance use, with input gathered through individual and small group listening sessions. They are also informed by interviews and small group discussions with experienced clinicians in the field. The panel discussion will explore special considerations for impacted youth and families related to a range of cross-cutting core treatment components, including engagement, safety, caregiver involvement, regulation, and others. Participants will leave this session with a general understanding of the complex relationship between substance use and T/CSE, recognition of special considerations with impacted youth and families, and intervention strategies for working with youth and families impacted by both T/CSE and problematic substance use.