Philosophiae Doctor - PhD / Adolescence, a critical developmental period, requires a certain level of adjustment and may negatively impact youth psychosocial development. Unsurprisingly, adolescent substance use continues to be a major public global health concern. Additionally, some adolescents are immersed in various interpersonal relationships and exposed to various stressors daily, which may affect their psychological well-being and developmental trajectories. This research aimed to explore the experiences of interpersonal relationships, stress and coping, and determine substance use patterns, symptoms of two common mental disorders (depression and generalized anxiety) amongst adolescents who report using substances (legal and illegal) in low-income communities in South Africa by employing Bronfenbrenner’s bio-ecological theory and the person-process-context-time model as a theoretical lens.