Background: The Millennium Development Goals (MDGs), adopted by most nations in 2000, set specific targets for poverty reduction, addressing topics like hunger, education and health. The fourth MDG aims to reduce child mortality by two-thirds between 1990 and 2015. South Africa is one of 12 countries where child mortality has increased since the baseline in 1990. Aims: To investigate the reasons for increased child mortality in South Africa, and propose an answer to whether the country can reach the fourth MDG. Methods: The literature in this paper draws on the Lancet Series on Health in South Africa, South Africa's MDG Country Reports, the United Nations MDG Report 2010 and relevant articles from a non-systematic search in PubMed. Results: HIV/AIDS, neonatal causes and childhood infections are three major killers of children under five in South Africa. Despite fairly high coverage of health services to pregnant women and children, there are important gaps in coverage and quality of care, with high burden of mother-to-child transmission of HIV, complications of birth and suboptimal postnatal care. Inequities are resulting in a strained public health sector and disparities in social determinants for health. Interventions of improved intrapartum care and care for newborns, together with a scale-up of prevention-of-mother-to-child-transmission of HIV counts for most of the potential lives saved. Conclusions: The vast majority of under-five deaths in South Africa could be avoided if coverage and quality of existing interventions was improved. With commitment to priority actions, South Africa has the potential to achieve the fourth MDG.