Due to the optimization of medical treatment with combination antiretroviral therapy (cART), children living with perinatally acquired HIV (PHIV) are now growing up into adulthood with a chronic disease, accompanied by its own challenges. These challenges include an increased risk of psychosocial problems, such as psychological distress, lower levels of social functioning, poorer academic functioning and decreased sexual health compared to healthy children. This thesis focusses on the potential presence, extent, and course of the challenges of children and adolescents living with PHIV. Specifically, the aim of this thesis is to evaluate cognitive development, fatigue, sexual development, and health-related quality of life of children and adolescents living with PHIV. We evaluated these outcomes through systematic reviews and studies of the NeurOlogical Visual and CognitivE performance (NOVICE) cohort, which was set up in the Amsterdam University Medical Centers, location Academic Medical Center, the Netherlands. The studies in this thesis show generally good long-term outcomes of children and adolescents with well-treated PHIV, yet remaining concerns include their cognitive development (specifically executive functioning), cognitive fatigue and possibly delayed sexual development. Our findings emphasize the importance of starting treatment with cART as early as possible, especially in low-to-middle income countries where this is not yet the case. It also emphasizes the importance of integrative care, specifically including the monitoring and guidance of cognitive problems, cognitive fatigue, and sexual development of children and adolescents with PHIV.