The association between hippocampal sclerosis (HS) and epilepsy has been known for almost two centuries. For many years, HS was studied in postmortem series; however, since the mid-20th century, surgical specimens from temporal lobe resections have provided important new knowledge. HS is the most common pathology underlying drug-resistant mesial temporal lobe epilepsy (MTLE), a syndrome with a characteristic history and seizure semiology. In the early 1990s, it was recognized that magnetic resonance imaging (MRI) could detect HS. The standard MRI protocol for temporal lobe abnormalities uses coronal slices perpendicular to the long axis of the hippocampus. The MRI features of HS include reduced hippocampal volume, increased signal intensity on T2-weighted imaging, and disturbed internal architecture. The histopathologic diagnosis of HS is usually straightforward, with neuronal loss and chronic fibrillary gliosis centered on the pyramidal cell layer. There are several patterns or subtypes of HS recognized from surgical series based on qualitative or quantified assessments of regional neuronal loss. The pathologic changes of HS include granule cell dispersion, mossy fiber sprouting, and alterations to interneurons. There may also be more extensive sclerosis of adjacent structures in the medial temporal lobe, including the amygdala and parahippocampal gyrus. Subtle cortical neuropathologies may accompany HS. The revised classification of dysplasias in epilepsy denotes these as focal cortical dysplasias type IIIa. Sometimes, HS occurs with a second lesion, either in the temporal lobe or extratemporal, most often ipsilateral to the HS. HS on preoperative MRI strongly predicts good seizure outcome following temporal lobe resection (TLR). If adequate MRI shows no structural correlate in patients with MTLE, functional imaging studies are valuable, especially if they are in agreement with ictal electroencephalography (EEG) findings. Focal hypometabolism on 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) ipsilateral to the symptomatic temporal lobe predicts a good surgical outcome; the added value of 11C-Flumazenil-PET (FMZ-PET) and proton magnetic resonance spectroscopy (MRS) is less clear. Surgical methods have evolved, particularly resecting less tissue, aiming to preserve function without compromising seizure outcome. Around two thirds of patients operated for MTLE with HS obtain seizure freedom. However, the best surgical approach to optimize seizure outcome remains controversial.