The ketogenic diet (KD) is a high-fat and low carbohydrate diet with an established efficacy to treat refractory epilepsy. Lipids, particularly fatty acids, are nutrients which provide the most important part of the caloric intake under the KD. It has been suggested that the 'high-fat' component of the KD plays a role in its anticonvulsant properties. It has been shown experimentally that polyunsaturated fatty acids alone (PUFA) exhibit anticonvulsant properties. But clinical trials in epilepsy using PUFA have failed to show any effect. This discrepancy can be explained by recent experimental data. Several experimental studies have suggested that PUFA may support the efficacy of the KD. PUFA may exhibit anticonvulsant properties via various mechanisms such as a modification of the composition of the CNS cell membranes, stimulation of nuclear receptor such as PPAR and by attenuating inflammation. Most of these hypotheses have evolved from experimental studies. However, it remains necessary to prove the role of PUFA in the KD, and therefore, further studies on this subject are needed. A better understanding of the underlying mechanisms may lead to the design new dietary treatment such as more liberal rules for KD or KD formula with a higher efficacy.