South Africa is one of only 12 countries in which mortality rates for children have increased since the baseline for the Millennium Development Goals (MDGs) in 1990. Continuing poverty and the HIV/AIDS epidemic are important factors. Additionally, suboptimum implementation of high-impact interventions limits programme effectiveness; between a quarter and half of maternal, neonatal, and child deaths in national audits have an avoidable health-system factor contributing to the death. Using the LiST model, we estimate that 11,500 infants' lives could be saved by effective implementation of basic neonatal care at 95% coverage. Similar coverage of dual-therapy prevention of mother-to-child transmission with appropriate feeding choices could save 37,200 children's lives in South Africa per year in 2015 compared with 2008. These interventions would also avert many maternal deaths and stillbirths. The total cost of such a target package is US$1.5 billion per year, 24% of the public-sector health expenditure; the incremental cost is $220 million per year. Such progress would put South Africa squarely on track to meet MDG 4 and probably also MDG 5. The costs are affordable and the key gap is leadership and effective implementation at every level of the health system, including national and local accountability for service provision.