Increasing antibiotic resistance is one of the leading problems in the Public Agenda worldwide. In the last 20 years, the pace of antimicrobial drug development has markedly slowed leading to a dramatic world situation. Infections with antibiotic-resistant microorganisms have been associated with increased length of stay, mortality and costs. Improving antimicrobial prescribing is one of the tools in our hands to optimize the outcomes of patients with moderate to severe infections and control the emerging of resistance. Several clues to improve antimicrobial prescribing are provided as a key-messages decalogue.