MR imaging allows the in vivo detection of hippocampal sclerosis (HS) and has been instrumental in the delineation of the syndrome of mesial temporal lobe epilepsy with HS (mTLE-HS). MR features of HS include hippocampal atrophy with an increased T2 signal. Quantitative MR imaging accurately reflects the degree of hippocampal damage.Ictal single photon emission computed tomography (SPECT) in mTLE-HS shows typical perfusion patterns of ipsilateral temporal lobe hyperperfusion, and ipsilateral frontoparietal and contralateral cerebellar hypoperfusion. Interictal 18fluoro-2-deoxyglucose positron emission tomography (PET) shows multiregional hypometabolism, involving predominantly the ipsilateral temporal lobe. 11C-flumazenil PET shows hippocampal decreases in central benzodiazepine receptor density. Future strategies to study the etiology and pathogenesis of HS should include longitudinal MR imaging studies,MR studies in families with epilepsy and febrile seizures, stratification for genetic background, coregistration with SPECT and PET, partial volume correction and statistical parametric mapping analysis of SPECT and PET images.