Critically ill patients are typically polymedicated and therefore at a high risk for potential drug interactions. Clinical consequences of drugs interactions vary in severity from mild to lethal events. Since infection is an important issue in the Intensive Care Unit (ICU), a significant number of patients will receive an antimicrobial at some stage during their ICU admission. Therefore an adequate knowledge about possible interactions between antimicrobials and other drugs is necessary, since it may not only impact on the effectiveness of the antimicrobial but also in the incidence of drug adverse events. This review describes important drug interactions involving antimicrobials in the critically ill patient.