A majority of current pharmacokinetic and pharmacodynamic data are generated from studies in healthy volunteers and stable patients with single organ dysfunction. However, critically ill patients differ from other patients because of the complex and unstable nature of their illness. Critical illness results in multiple changes that alter drug disposition in the body. As organs fail, so the pharmacokinetic processes of absorption, distribution, and elimination are affected. These alterations change the way drugs are handled by the body, often in unpredictable ways. Furthermore, multiple organ failure may also induce changes in the sensitivity of the target organs to a specific drug. Another problem that arises during treatment of a critically ill concerns polypharmacy, which may sometimes include concomitant administration of more than 20 drugs in a single patient. Evidence suggests that deep understanding of basic pharmacokinetic principles associated with therapeutic drug monitoring might decrease toxicity and could be cost-effective. The aim of this review article is threefold: 1. to describe basic pharmacokinetic principles, 2. discuss their changes during critical illness and 3. emphasize possible alternatives concerning an individualized therapeutic plan design. Its application in every day clinical practice might aid in early intervention, in cases of possible drug-to-drug or drug-to-patient adverse reactions and finally, could decrease morbidity and/or mortality of patients during their stay in the Intensive Care Unit.