About one-third of patients with epilepsy are in part or fully refractory to treatment, creating an enormous medical, social, and economic burden. Thus, an essential aspect of any future prioritization is the need to develop new or improve existing antiseizure therapies for patients with refractory epilepsy. Efforts should include analysis of sequencing data for patients who fail to show adequate improvement following surgical intervention to determine whether there are shared risk factors, as well as those who successfully respond. Approaches that deserve consideration in this regard include conventional drug development, selection of surgical patients, and genetic analysis of both responsive and refractory patients. Toward this end, several new drugs have entered clinical use following FDA approval, including cannabidiol for Dravet and Lennox-Gastaut syndromes,54,55 nasally administered midazolam for seizure clusters,56 stiripentol for Dravet syndrome,57 and everolimus for seizures in patients with tuberous sclerosis complex.58 In addition, new treatment approaches for specific epilepsies are under investigation with novel or disease-specific targets, including AMPA receptors containing the TARPγ8 subunit, expressed predominantly in the temporal lobe and of potential relevance to mesial temporal lobe epilepsy59; KCNQ (Kv7) potassium channels implicated in KCNQ2 developmental and epileptic encephalopathy60; and serotonin systems, representing a target of fenfluramine, which have been reported to cause seizure reduction in patients with Dravet syndrome.61 New routes of drug administration are also being explored.62 It will be important to carefully evaluate the utility of these new medications in refractory epilepsy beyond the initial indications for which they are tested or approved.