Antimicrobial resistance (AMR) as a serious public health threat was globally acknowledged by WHO in 2015, through the launch of the Global Action Plan (GAP). With a limited number of new antibiotics in the developmental pipeline, many countries are in the process of establishing strategies for antimicrobial stewardship (AMS). Within each country, different healthcare challenges have contributed to AMR. This has also shaped individual AMS strategies and policies. In South Africa (SA), there is a high burden of infectious diseases, mainly of bacterial origin. In addition, SA also has the highest number of people living with human immunodeficiency virus (HIV) globally. According to the 2019 statistics, there are approximately 7.97 million people living with HIV in SA. Together with this, SA has the fourth largest tuberculosis population globally. Other important challenges include poverty, malnutrition, a high burden of non-communicable diseases, and a dire shortage of trained healthcare professionals (e.g. clinicians, pharmacists, and nurses).