Despite the continued development and release of new antiepileptic drugs (AEDs), 20-30% of all patients with epilepsy do not respond to conventional therapy or have related side effects that preclude their continued use. Presently, the most important AEDs used in paediatric population are: phenytoin, carbamazepine, valproic acid, vigabatrin, lamotrigine and topiramate. Their mechanisms of action are only partially known. The side-effects of the common antiepileptic drugs are exhaustively described but the strategies to avoid them are still unsatisfactory. Among alternative therapies used for the “drugs resistant epilepsy”, the nutritional approach defined “ketogenic diet” is one of the most promising and several reports confirmed its efficacy especially in children defined “drug resistant”. However, after more than 80 years of its applications, the mechanism of action, the long-term side-effects and the indications of use of the ketogenic diet are not satisfactory clarified. The purpose of this work is to review recent advances in nutritional and pharmacological management of childhood epilepsy comparing the history, the mechanisms of action, the indications, and the side effects of the ketogenic diet and the principal antiepileptic drugs in order to assess the links between the two kind of approaches.