Seizures cannot be medically controlled in approximately 40% of people with epilepsy. Although we are beginning to understand how to better treat certain seizure types, we still do not know the regulatory events that determine antiepileptic drug resistance. Proposed pathoetiologic mechanisms include altered expression of drug targets (i.e., receptor or ion channel modifications), endothelial drug transporter activation (i.e., increasing drug clearance), or intrinsic severity factors. The latter hypothesis results from an often confirmed clinical observation, that seizure severity is a reliable predictor for the development of pharmacoresistance (PR) in epilepsy. Herein, we propose, that genome modifications that do not involve changes to the DNA sequence per se (i.e., epigenetic changes) could confer PR in patients with epilepsy. Seizures cause excessive neuronal membrane depolarization, which can influence the cellular nucleus; we thus hypothesize that seizures can mediate epigenetic modifications that result in persistent genomic methylation, histone density, and posttranslational modifications, as well as noncoding RNA-based changes. Although experimental evidence is lacking in epilepsy, such mechanisms are well characterized in cancer, either as a result of anticancer drugs themselves or cancer-related intrinsic signals (i.e., noncoding RNAs). We suggest that similar mechanisms also play a role in PR epilepsies. Addressing such epigenetic mechanisms may be a successful strategy to increase the brain's sensitivity to antiepileptic drugs and may even act as disease-modifying treatment.