Although there are many types of epilepsy of both genetic and acquired forms, temporal lobe epilepsy (TLE) with hippocampal sclerosis is probably the single most common human epilepsy, and the one most intensely studied. Despite a wealth of descriptive data obtained from patient histories, imaging techniques, electroencephalographic recording, and histological studies, the epileptogenic process remains poorly understood. Progress toward understanding the etiology of an acquired neurological disorder is largely dependent on the degree to which experimental animal models reflect the human condition. Recent observations suggest that significant disparities exist between the features of human TLE with hippocampal sclerosis and those of animal models that involve prolonged status epilepticus to initiate the epileptogenic process. TLE most commonly involves patients with focal seizures who exhibit limited and often asymmetrical brain damage, did not experience status epilepticus prior to the onset of epilepsy, and who appear relatively normal on neurological examination. Conversely, animals subjected to prolonged status epilepticus exhibit severe brain damage, behavioral abnormalities, and frequent generalized seizures. In addition, although many TLE patients exhibit an atrophic hippocampus that may, or may not, be a source of spontaneous seizures, hippocampal damage in animals subjected to status epilepticus is an inconsistent and often minor part of a much greater constellation of damage to other brain structures. Furthermore, many patients exhibit developmental structural abnormalities that presumably play a role in the clinical etiology, whereas most animal models involve severe insults in initially normal laboratory rats. Although much has been learned using the current animal models, the available data suggest the need for a critical reappraisal of the assumptions underlying their use, and the need to develop experimental preparations that may more closely model the human epileptic state.