For several decades, researchers from the South African Medical Research Council have made invaluable contributions towards improving the health of the population through the analysis and interpretation of cause of death data. This article reflects the mortality trends in pre-and post-apartheid South Africa (SA), and describes efforts to improve vital statistics, innovations to fill data gaps, and studies to estimate the burden of disease after adjusting for data deficiencies. The profound impact of HIV/AIDS, particularly among black African children and young adults, is striking, within a protracted epidemiological transition and the current reversals of multiple epidemics. Over the next 20 years, it will be important to sustain and enhance the country's capacity to collect, analyse and utilise cause of death data. SA needs to support development in the region, harnessing new data platforms and approaches such as including verbal autopsy tools in the official system and improving data linkage.