Doctors Without Borders (MSF) marks 20 years of uninterrupted humanitarian work in South Africa in 2020. MSF is recognised as one of the pioneers of providing Antiretroviral Treatment (ART) in the public sector and started first HIV programmes in 1999 which led us to develop deep roots in the HIV/AIDS and tuberculosis (TB) response in South Africa and internationally. Up until today, our programmes and interventions in South Africa have primarily focused on developing new testing and treatment strategies for HIV/AIDS and TB. Over the years, MSF has established additional projects since people in South Africa continue to struggle with a number of humanitarian issues, including widespread violence and sexual gender-based violence (SGBV) in particular while vulnerable asylum seekers, refugees and migrants continue to suffer healthcare exclusion. These projects focus on responding to sexual violence as a medical emergency, the health needs of vulnerable migrants as well as capacities in emergency response. We also continue to push for better access to affordable lifesaving drugs through advocacy and partnerships with local civil society organisations. To mark the 20-year milestone, we offer a timeline of our activities and reflect on 10 critical moments of our interventions in South Africa.