Objective To update the 2004 American Academy of Neurology guideline for managing treatmentresistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods 2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results Forty-two articles were included. Recommendations The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not firstline treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month–16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month–4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidencebased assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons =4 years of age and perampanel as monotherapy received FDA approval.