Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.