The two objectives of ensuring early appropriate antimicrobial treatment for septic patients on the intensive care unit (ICU), and limiting emergence and spread of antimicrobial resistance are both complicated and potentially conflicting. Increasingly unpredictable resistance, particularly amongst Gram-negative bacteria, through both local selection and transmission, and importation of globally successful resistant clones encourages the use of broad-spectrum empiric antimicrobials for septic patients, including in combination. This may lead to a vicious cycle whereby increasing antibiotic use increases resistance, which in turn leads to higher levels of inappropriate therapy. In response, the multi-disciplinary ICU-team implements infection prevention and control, and antimicrobial stewardship programmes. Antimicrobial stewardship programmes provide interventions and guidance to optimize appropriate therapy,whilelimiting unnecessary use through a variety of measures. The development of rapid molecular testing for bacterial identification and antimicrobial susceptibility prediction could potentially bring useful microbiological information to the bedside at the time of therapeutic decision making.