The emergence of antimicrobial resistance (AMR) is a major concern worldwide and already compromises treatment effectiveness and control of several bacterial sexually transmitted infections (STIs). Neisseria gonorrhoeae and Mycoplasma genitalium are evolving into so-called superbugs that can become resistant, both in vitro and clinically, to essentially all antimicrobials available for treatment, causing exceedingly difficult-to-treat or untreatable STIs and threatening global public health. Widespread AMR in these bacteria is likely to persist and even worsen in the future, owing to the high number of infections, widespread and uncontrolled use of antimicrobials, limited surveillance of AMR and clinical failures, as well as the extraordinary capacity of these bacteria to develop AMR. This development would not only result in an increased prevalence of N. gonorrhoeae and M. genitalium infections but also in a considerably increasing number of severe complications affecting reproductive health. To combat this threat, clinicians need to be aware of the current guidelines on diagnostic procedures, recommended treatment regimens, as well as therapeutic options for multidrug-resistant bacteria. AMR testing needs to be more frequently performed, inform treatment decisions and elucidate how AMRs compromise treatment effectiveness, guiding research for effective future therapies.