Approximately 50% of patients with newly diagnosed epilepsy achieve immediate remission, and up to 50% enter terminal remission with first-generation antiepileptic drugs. However, 20–30% of cases are still refractory to current treatments. This population is the target of newer antiepileptic drugs and other compounds in development. The licensing of newer antiepileptic drugs represents an advance in the development of more manageable products and the control of several disturbing adverse drug reactions of the older compounds. However, despite the development of several new antiepileptic drugs, the efficacy and tolerability of drug treatment of epilepsy has not substantially improved in terms of effectiveness and risk–benefit and cost–benefit profiles. Newer antiepileptic drugs are, at best, equivalent in efficacy to their predecessors, but some of them are more manageable and better tolerated. However, the use of a first-generation compound at low doses in newly diagnosed patients is still preferable because the disease can be as well-controlled and the incidence of intolerable side effects is minimized. Newer generation compounds should be used as alternative treatments in patients who are nonresponding to first-generation drugs and in those for whom these drugs are contraindicated or poorly tolerated. As an exception, some new-generation drugs are a valuable option in the presence of comorbidities known to respond to these products or in patients with selected epilepsy syndromes. In light of the heterogeneity and the complexity of the mechanisms underlying epileptic seizures, the future of drug development will be the discovery of drugs efficacious for the treatment of selected epilepsy syndromes or, more specifically, targeting genetic defects leading to molecular abnormalities.