Results from add-on antiepileptic drug (AED) trials performed in patients with chronic refractory epilepsy cannot be directly extrapolated to newly diagnosed patients because of fundamental differences in disease characteristics between the two patient populations. This article reviews the results of randomized, controlled trials of AEDs as monotherapy in newly diagnosed patients, focusing on the newer drugs. None of the newer AEDs has shown superior efficacy when tested against established agents for the treatment of partial seizures and generalized tonic-clonic seizures, the most common seizure types. Some of the newer drugs have shown good tolerability, resulting in better overall effectiveness in the case of lamotrigine over carbamazepine and oxcarbazepine over phenytoin, whereas vigabatrin and remacemide were demonstrated to have inferior efficacy compared with carbamazepine. The difficulty in detecting differences in efficacy among the AEDs might be attributed to the strategies underlying their development and the characteristics of the patient population under investigation. A better understanding of the pathophysiology of seizures and its relationship to epileptogenesis, and the use of more innovative strategies to identify new molecular targets, are needed for the development of a new generation of more effective AEDs that are not merely antiseizure but will hinder or reverse the deleterious processes that underlie the genesis of refractory epilepsy.