In addition to new medications, more effort is needed to understand the mechanisms of pharmacoresistance in order to overcome refractoriness to ASMs. To this end, new animal models together with humanized models in vitro based on genetic data may provide an opportunity to explore mechanisms of resistance for those specific models with clear seizure phenotypes for which the patient is known to be refractory to treatment with conventional anticonvulsants. Work in this area would benefit from integration of information about new targets into existing efforts to develop new medications that are effective against refractory seizures. In addition to traditional targets such as ion channels, neurotransmitter receptors, and neurotransmitter transporters, important targets include mTOR and related pathways, the extracellular matrix, oxidative stress, anti-inflammatory pathways, neurosteroid systems, microRNAs, and epigenetic targets include histone deacetylase.30,31,63-67 Cell replacement strategies to introduce engineered cells that can support or release neuroactive substances and oligonucleotide approaches to regulate specific genes for therapeutic gain are also opportunities to identify new ways to treat refractory epilepsy. Moreover, clarification of the mechanisms underlying the ketogenic diet might identify metabolic and lipid targets that are relevant, the role of the gut microbiota,68 and allow a “ketogenic diet in a pill” treatment strategy for refractory epilepsy.