Adolescents face many challenges that can affect their psychosocial wellbeing. These include: the capacity for independence and self-management; an understanding of and ability to cope with potential stigma or discrimination; dealing with family stress, illness or death, orphanhood, and poverty; progress through education with possible cognitive impairment; disclosure to others for emotional and practical support; and an emerging sexuality. Adolescents require support in developing skills to independently manage their health, achieving acceptance amongst peers, and navigating sexuality and intimate relationships. This support should not only be provided through medical and allied health staff, but also through fostered peer support networks that provide a sense of belonging and connectedness, as well as opportunities to discuss challenges encountered in an understanding and compassionate environment. Serial screening for mental health and substance use disorders is an integral component to the holistic care of adolescents. Effective psychosocial support can have a positive impact on ART adherence, engagement in care, academic performance, and interpersonal relationships; as well as adjusting to the stigma and secrecy that may arise from having HIV infection (including complex family dynamics and inter-generational HIV-related issues).