Prompt optimal antimicrobial treatment in critically ill patients is mandatory and must be achieved not only in terms of spectrum of activity, but also in terms of exposure at the infection site. Plasma profile of antimicrobial agents may represent a valid surrogate marker of drug exposure and allow to identify the correct dosage for a given drug. However, in the critically ill patients the pharmacokinetic behavior of antimicrobials may be altered by some very peculiar pathophysiological conditions, so that dosages significantly different from those used in clinically stable patients or from those originally studied in healthy volunteers for regulatory purposes may often be needed in order to ensure optimal plasma drug exposure in such population. This is especially true for hydrophilic antimicrobials (aminoglycosides, beta-lactams, glycopeptides, lipopeptides, echinocandins, fluconazole, acyclovir, ganciclovir) whose volume of distribution and clearance may be significantly altered by these conditions. These aspects are particularly relevant in patients with severe sepsis or with septic shock for whom the time for being considered as a special population to be studied apart from the general population has probably come. From the healthcare system perspective, this means that individualization of antimicrobial therapy by means of a real time therapeutic drug monitoring coupled with clinical pharmacological advice should be considered an invaluable tool for optimizing antimicrobial therapy and for the containment of microbial resistance in this setting.