The introduction of antibiotics to human medicine revolutionized health care like few other innovations. Yet, the benefits conveyed by the availability these safe and effective drugs are threatened by the rapid spread and emergence of antimicrobial resistance (AMR). The epidemiology of AMR is complex and influenced by many different factors. It is, however, clear that antibiotic use in humans is a key driver of AMR. Overall and inappropriate antibiotic use varies widely among settings, for reasons that are incompletely understood. Antibiotic stewardship (ABS) aims to reduce inappropriate antibiotic use, for example through public campaigns in the outpatient setting or dedicated ABS teams in hospitals. ABS faces, however, many challenges such as a lack of a clear consensus of what constitutes inappropriate use and the absence of solid evidence on how best to reduce antibiotic selection pressure. In addition to ABS, other strategies that prevent transmission are needed.