Therapeutic drug monitoring (TDM) has been recognized as a useful guide in the clinical management of patients with epilepsy, in particular those on therapy with traditional antiepileptic drugs (AEDs). The demonstration of significant drug interactions and the introduction of the concept "therapeutic range" have also contributed to the view that monotherapy should be considered the "gold standard" in the treatment of epilepsy. Ten new AEDs have been approved and released to the market in the last fifteen years. The most obvious consequence has been an increased number of patients on polytherapy. In general, newer AEDs have better and more predictable pharmacokinetics than older AEDs and usually show lower risk of interactions leading to toxicity as well as large therapeutic indexes. This pragmatic review focuses on practical suggestions about the potential clinical usefulness of TDM of newer AEDs in relation to their mechanism of action and pharmacokinetic characteristics and in response to patient-specific problems. Overall, the usefulness of TDM of newer AEDs seems to be limited and its indiscriminate use is not justified. However, in selected cases or in response to a specific clinical question, a wise use of TDM of some new AEDs could represent a useful tool in the management of epileptic patients. Exceptions are thus represented by special conditions such as renal failure, dialysis, ascertainment of non-compliance, and pregnancy. For some new AEDs, TDM could be selectively and properly used in response to a single patient-specific pharmacokinetic or pharmacodynamic issue.