ABSTRACTSeveral animal models are discussed in order to outline features of difficult‐to‐treat or drug‐resistant epilepsy. These models can be categorised as those which show a poor response to different antiepileptic drugs and those in which subgroups of drug‐resistant animals are selected, based on interindividual differences. Non‐responders to antiepileptic drugs have been described in the amygdala kindling model, as well as the chronic phase of post‐status epilepticus models. Epileptic dogs which do not respond to standard antiepileptic drugs may serve as a translational model to provide a more clinical environment for drug testing. Drug resistance or a poor response to several antiepileptic drugs has been reported for the 6‐Hz model, lamotrigine‐pretreated kindled rats, pentylentetrazole‐induced seizures in rats pre‐exposed to pilocarpine, as well as following intrauterine exposure of rats to methylazoxymethanol. Using models to select non‐responders is highly time‐consuming and elaborate, limiting their use in routine drug‐screening procedures. Current efforts to identify biomarkers of drug resistance may simplify the selection process, e.g. replacing several weeks of seizure monitoring by a single imaging scan. Moreover, further elucidation of mechanisms of resistance may help to design a series of ex vivo or in vitro screening procedures in order to evaluate whether a test compound is affected.