The use of antibiotics since mid-twentieth century significantly reduced morbidity and mortality worldwide. However, the emergence of antimicrobial resistance has made therapy of infectious diseases a challenging task for physicians, who must provide therapeutic, rational and evidence-based options aiming to improve their patients health. This review provides an overview on how serious the current situation and the paramount role is that health systems must play in supporting healthcare professionals and educating patients in order to achieve rational use of these medications.