Understanding the natural history of and factors associated with pharmacoresistant epilepsy provides the foundation for formulating mechanistic hypotheses that can be evaluated to drive the development of novel treatments. This article reviews the modern definition of drug-resistant epilepsy, its prevalence and incidence, risk factors, hypothesized mechanisms, and the implication of recognizing pharmacoresistance in therapeutic strategies. This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.