Infants and children of all ages treated in intensive care units are exposed to a multitude of drugs that are used in the majority of cases in an off-label manner. Predicting drug disposition and prescribing the appropriate dosage regimen are of importance to reach precision medicine goals. In general, drug disposition and action are determined by pharmacokinetics, pharmacodynamics and pharmacogenetics. The major determinants of pharmacokinetics are absorption, distribution, metabolism and excretion (ADME). In neonates, infants and children, drug disposition is determined by developmental changes (maturational factors), and underlying diseases, treatment modalities, concomitant medications, genetics and the physicochemical properties of administered drugs (non-maturational factors). For this reason, a multifactorial approach is needed to achieve a level of targeted pharmacotherapy that is both effective and safe. The maturational factors in drug disposition are essential to understand the dose/concentration and exposure-response relationship. However, non-maturational factors superimposed on ontogeny may change the dose/concentration and exposure-response relationship significantly due to dynamic changes in drug distribution or elimination.