Antimicrobial resistance (AMR) is a multifaceted, international public health problem, which poses a direct threat to the safety of the population of South Africa. A national response is required to complement the development of a global plan, as articulated in the WHO’s draft resolution EB134/37 “Combating antimicrobial resistance including antibiotic resistance”, adopted by theWorld Health Assembly in May 2014. The overuse of antimicrobials is driving resistance. A return to appropriate, targeted antimicrobial use in humans, animals and the environment is critical if we are to conserve the antimicrobial armamentarium. Various interventions have been put in place to address antimicrobial resistance in South Africa. However, these are insufficient to effectively tackle the threat faced by the country. The strengths of the current system are outweighed by its weaknesses.