Mesial temporal lobe epilepsy (TLE) is a subtype of epilepsy in which individuals present with seizure semiology and electroencephalographic characteristics that point to an ictal onset in mesial temporal structures. The diagnosis of TLE involves different etiologies, the most common being hippocampal sclerosis, but up to 20% of TLE patients have no detectable structural lesions on modern MRIs. A variability of antiepileptic drug response and surgical prognosis is observed in TLE. The understanding of the differences among patients with TLE can facilitate the development of individualized and more efficient therapeutics. In this study, we will address the recent contributions of neuroimaging, neurophysiology, genetics and histopathology to the comprehension of the spectrum of TLE with and without MRI signs of hippocampal sclerosis and how the advances in these areas have helped to improve surgical treatments.