Surgery is a well established option in treating patients with medically intractable epilepsy. Better outcomes are achieved in surgical candidates who have magnetic resonance imaging (MRI) lesions present prior to surgery. In a minority of cases, no discernible MRI lesion is evident prior to surgery (nonlesional). The most commonly documented histopathologic findings in this clinical setting are focal cortical dysplasias, nonspecific gliosis, hippocampal sclerosis and no identifiable light microscopic alteration. There are a number of potential explanations for the absence of light microscopic findings in a subset of MRI-negative or nonlesional epilepsy patients related to the surgical resection being off-target, pathologic tissue sampling, interobserver and intraobserver variability in the diagnosis of certain pathologies, evolving pathology and lesions that are beyond light microscopic detection. This paper reviews the definition of nonlesional epilepsy, the pathologies encountered in this setting, possible explanations for the absence of apparent light microscopic abnormalities in some cases, and future directions.