High mortality and morbidity rates associated with severe infections in the critically ill continue to be a significant issue for the healthcare system. In view of the diverse and unique pharmacokinetic profile of drugs in this patient population, there is increasing use of therapeutic drug monitoring (TDM) in attempt to optimize the exposure of antibiotics, improve clinical outcome and minimize the emergence of antibiotic resistance. Despite this, a beneficial clinical outcome for TDM of antibiotics has only been demonstrated for aminoglycosides in a general hospital patient population. Clinical outcome studies for other antibiotics remain elusive. Further, there is significant variability among institutions with respect to the practice of TDM including the selection of patients, sampling time for concentration monitoring, methodologies of antibiotic assay, selection of PK/PD targets as well as dose optimisation strategies. The aim of this paper is to review the available evidence relating to practices of antibiotic TDM, and describe how TDM can be applied to potentially improve outcomes from severe infections in the critically ill.