Drug-resistant epilepsy is a prevalent problem despite the multiple antiepileptic drug (AED) options available. Despite variations in the definition of drug resistance, clinicians can identify risk factors for AED resistance. Drug-resistant partial epilepsy should be referred early to an epilepsy surgery center. Mimics of drug-resistant epilepsy abound and cause diagnostic confusion. Rapid advances in epilepsy research and pharmacogenomics are providing new insight into the mechanisms of drug resistance and tolerance. Rational AED strategies and promising interventions to treat or prevent drug resistance will reduce the impact on the patient.