The use of antiepileptic drugs (AEDs) in monotherapy is always preferred to a polytherapy regimen because monotherapy facilitates drug compliance, is associated with a lower risk of toxicity, and is less costly. In addition, the yield of polytherapy to render a patient seizure-free when monotherapy regimens did not is relatively low. The available data derived from randomized controlled trials suggest that standard and new AEDs appear to display comparable antiepileptic efficacy but they differ with respect to tolerability and toxicity, which may be related to their pharmacodynamic and pharmacokinetic properties. New AEDs appear to be better tolerated than standard AEDs and to have fewer pharmacokinetic interactions than standard AEDs. In this article, we review the advantages of using AEDs in monotherapy in patients with newly diagnosed and refractory epilepsies, focusing on the individual properties of the drugs that may make them more appropriate in various patient groups.