Surgery has become the standard of care for patients with intractable temporal lobe epilepsy, with anterior temporal lobe resection the most common operation performed for adults with hippocampal sclerosis. This procedure leads to significant improvement in the lives of the overwhelming majority of patients. Despite improved techniques in neuroimaging that have facilitated the identification of potential surgical candidates, the short-term and long-term success of epilepsy surgery has not changed substantially in recent decades. The basic surgical goal, removal of the amygdala, hippocampus, and parahippocampal gyrus, is based on the hypothesis that these structures represent a uniform and contiguous source of seizures in the mesial temporal lobe epilepsy (MTLE) syndrome. Recent observations from the histopathology of resected tissue, preoperative neuroimaging, and the basic science laboratory suggest that the syndrome is not always a uniform entity. Despite clinical similarity, not all patients become seizure-free. Improving surgical outcomes requires a re-examination of why patients fail surgery. This review examines recent findings from the clinic and laboratory. Historically, we have considered MTLE a single disorder, but it may be time to view it as a group of closely related syndromes with variable type and extent of histopathology. That recognition may lead to identifying the appropriate subgroups that will require different diagnostic and surgical approaches to improve surgical outcomes.