Since the 2009 Lancet Health in South Africa Series, important changes have occurred in the country, resulting in an increase in life expectancy to 60 years. Historical injustices together with the disastrous health policies of the previous administration are being transformed. The change in leadership of the Ministry of Health has been key, but new momentum is inhibited by stasis within the health management bureaucracy. Specific policy and programme changes are evident for all four of the so-called colliding epidemics: HIV and tuberculosis; chronic illness and mental health; injury and violence; and maternal, neonatal, and child health. South Africa now has the world's largest programme of antiretroviral therapy, and some advances have been made in implementation of new tuberculosis diagnostics and treatment scale-up and integration. HIV prevention has received increased attention. Child mortality has benefited from progress in addressing HIV. However, more attention to postnatal feeding support is needed. Many risk factors for non-communicable diseases have increased substantially during the past two decades, but an ambitious government policy to address lifestyle risks such as consumption of salt and alcohol provide real potential for change. Although mortality due to injuries seems to be decreasing, high levels of interpersonal violence and accidents persist. An integrated strategic framework for prevention of injury and violence is in progress but its successful implementation will need high-level commitment, support for evidence-led prevention interventions, investment in surveillance systems and research, and improved human-resources and management capacities. A radical system of national health insurance and re-engineering of primary health care will be phased in for 14 years to enable universal, equitable, and affordable health-care coverage. Finally, national consensus has been reached about seven priorities for health research with a commitment to increase the health research budget to 2·0% of national health spending. However, large racial differentials exist in social determinants of health, especially housing and sanitation for the poor and inequity between the sexes, although progress has been made in access to basic education, electricity, piped water, and social protection. Integration of the private and public sectors and of services for HIV, tuberculosis, and non-communicable diseases needs to improve, as do surveillance and information systems. Additionally, successful interventions need to be delivered widely. Transformation of the health system into a national institution that is based on equity and merit and is built on an effective human-resources system could still place South Africa on track to achieve Millennium Development Goals 4, 5, and 6 and would enhance the lives of its citizens. Copyright © 2012 Elsevier Ltd. All rights reserved.