<p>Critically ill patients are susceptible to serious infections due to their compromised conditions and extensive use of medical devices, often requiring empiric broad-spectrum antimicrobial therapy. Failure of antimicrobial therapy in this vulnerable population has a direct impact on the patient’s survival; hence, selecting the optimal dosage is critical. This population, however, exhibits complex and diverse disease-related physiological changes that can markedly alter antimicrobial disposition. Inflammatory cytokines overexpressed in the systemic inflammatory response syndrome increase vascular permeability, leading to higher volume of distribution for hydrophilic antimicrobials. These cytokines also downregulate metabolic enzyme activities, reducing the clearance of their substrates. Hypoalbuminemia can increase the volume of distribution and clearance of highly protein-bound antimicrobials. Acute kidney injury decreases, while augmented renal clearance increases the clearance of antimicrobials primarily excreted by the kidneys. Furthermore, continuous renal replacement therapy and extracorporeal membrane oxygenation used in critical illness substantially affect antimicrobial pharmacokinetics. The complex interplay of multiple factors observed in critically ill patients poses a significant challenge in predicting the pharmacokinetics of antimicrobials. Therapeutic drug monitoring is the most effective tool to address this issue, and is proactively recommended for vancomycin, teicoplanin, aminoglycosides, voriconazole, β-lactams, and linezolid in critically ill patients. To streamline this process, model-informed precision dosing is expected to promote personalized medicine for this population.</p>