Over the past three decades, tremendous global progress in preventing and treating paediatric HIV infection has been achieved. This paper highlights the emerging health challenges of HIV-exposed uninfected (HEU) children and the ageing population of children living with HIV (CLHIV), summarises programmatic opportunities for care, and highlights currently conducted research and remaining research priorities in high HIV-prevalence settings such as South Africa. Emerging health challenges amongst HEU children and CLHIV include preterm delivery, suboptimal growth, neurodevelopmental delay, mental health challenges, infectious disease morbidity and mortality, and acute and chronic respiratory illnesses including tuberculosis, pneumonia, bronchiectasis and lymphocytic interstitial pneumonitis. CLHIV and HEU children require three different categories of care: (i) optimal routine child health services applicable to all children; (ii) routine care currently provided to all HEU children and CLHIV, such as HIV testing or viral load monitoring, respectively, and (iii) additional care for CLHIV and HEU children who may have growth, neurodevelopmental, behavioural, cognitive or other deficits such as chronic lung disease, and require varying degrees of specialised care. However, the translation thereof into practice has been hampered by various systemic challenges, including shortages of trained healthcare staff, suboptimal use of the patient-held child's Road to Health book for screening and referral purposes, inadequate numbers and distribution of therapeutic staff, and shortages of assistive/diagnostic devices, where required. Additionally, in low-middle-income high HIV-prevalence settings, there is a lack of evidence-based solutions/models of care to optimise health amongst HEU and CLHIV. Current research priorities include understanding the mechanisms of preterm birth in women living with HIV to optimise preventive interventions; establishing pregnancy pharmacovigilance systems to understand the short-, medium- and long-term impact of in utero ART and HIV exposure; understanding the role of preconception maternal ART on HEU child infectious morbidity and long-term growth and neurodevelopmental trajectories in HEU children and CLHIV, understanding mental health outcomes and support required in HEU children and CLHIV through childhood and adolescence; monitoring HEU child morbidity and mortality compared with HIV-unexposed children; monitoring outcomes of CLHIV who initiated ART very early in life, sometimes with suboptimal ART regimens owing to medication formulation and registration issues; and testing sustainable models of care for HEU children and CLHIV including later reproductive care and support.