A broad spectrum of structural lesions can be histopathologically identified in surgical brain specimens obtained from patients with focal, therapy-refractory epilepsies. In our experience with 4512 tissue samples collected at the German Neuropathological Reference Center for Epilepsy Surgery, three clinicopathological entities are most common: mesial temporal sclerosis (40%), long-term epilepsy-associated tumors (27%), and malformations of cortical development (13%). Notwithstanding, a systematic histopathological and molecular-genetic analysis is mandatory to unravel the underlying pathogenic mechanism of epilepsy-associated lesions and may contribute to our current understanding of pharmacoresistance and epileptogenesis. However, an interdisciplinary approach is necessary to further explore predictive parameters with respect to postsurgical seizure relief and memory impairment, and also to identify new pharmacological targets.