South Africa has been engaged in pharmacovigilance (PV) activities to assess the impact of adverse drug reactions on public safety and health for 40 years. Activities have evolved from passive regulatory reporting to encompass active surveillance systems. The HIV and AIDS and TB epidemics stimulated pharmacoepidemiological research into the risks associated with medicines used in the standardised regimens of mass treatment programmes. Specific safety concerns, supported by robust local cohort data, have prompted major changes to national and international treatment policies. This chapter describes the expanding body of local knowledge and the historical and emergent surveillance systems that address the burden of drug-related harms, noting the challenges to health system responsiveness. The South African context presents a unique opportunity to characterise the scale and nature of such harms in mass HIV and AIDS and TB treatment programmes. The use of complex regimens at scale poses new PV challenges. There is an urgent need to develop cohesive, sustainable systems to support evidence-based decisions on appropriate regimen choices, while minimising medicine-associated risks. The increasing use of computerised clinical, laboratory and dispensing records, with unique patient identifiers facilitating data linkage, will increase PV surveillance capacity. A coherent national PV framework is an essential part of medicines policy, encompassing regulatory, programmatic and individual needs. Key pillars of this framework include: (i) consolidation and expansion of active and passive PV surveillance, optimising existing programmes; (ii) prioritising post-marketing monitoring within the new health products regulatory authority; and (iii) instilling a culture of active risk management in clinical practice through the creation of effective channels of communication and feedback into policy and practice.