Critically ill patients suffering from severe infections are prone to pathophysiological pharmacokinetic changes that are frequently associated with inadequate antibiotic serum concentrations. Minimum inhibitory concentrations (MICs) of the causative pathogens tend to be higher in intensive care units. Both pharmacokinetic changes and high antibiotic resistance likely jeopardize the efficacy of treatment. The use of extracorporeal circulation devices to support hemodynamic, respiratory, or renal failure enables pharmacokinetic changes and makes it even more difficult to achieve an adequate antibiotic dose. Besides a clinical response, antibiotic pharmacokinetic optimization is important to reduce the selection of strains resistant to common antibiotics. In this review, we summarize the present knowledge regarding pharmacokinetic changes in critically ill patients and we discuss the effects of extra-corporeal devices on antibiotic treatment together with potential solutions.