The increasing success of prevention of mother-to-child HIV transmission programmes means that in Africa, very large numbers of HIV-exposed, uninfected (HIV-EU) children are being born. Any health problems that these children may have will thus be of enormous public health importance, but to date have been largely neglected. There is some evidence that HIV-EU African children are at increased risk of mortality, morbidity and slower early growth than their HIV-unexposed counterparts. A likely major cause of this impaired health is less exposure to breast milk as mothers are either less able to breastfeed or stop breastfeeding early to protect their infant from HIV infection. Other contributing factors are parental illness or death resulting in reduced care of the children, increased exposure to other infections and possibly exposure to antiretroviral drugs. A broad approach for psychosocial support of HIV-affected families is needed to improve health of HIV-EU children. High quality programmatic research is needed to determine how to deliver such care.