Disease modification of epilepsy refers to the alleviation of epileptogenesis or comorbidities after genetic or acquired epileptogenic brain insults. There are currently 30 proof-of-concept experimental pharmacologic studies that have demonstrated some beneficial disease-modifying effects. None of these studies, however, has yet passed from the laboratory to the clinic. The International League Against Epilepsy and American Epilepsy Society working groups on antiepileptogenic (AEG) therapies recently released recommendations for conducting preclinical AEG studies, taking into account many of the critiques raised by previous study designs. One of the issues relates to the lack of analysis of AEG efficacy in both sexes. A review of the literature reveals that most of the preclinical studies have been performed using male rodents, whereas clinical study cohorts include both males and females. Therefore, it is important to determine whether sex differences should be taken into account to a greater extent than they have been historically at different phases of experimental studies. Here we address the following questions based on analysis of available experimental AEG studies: (a) whether sex differences should be considered when searching for novel AEG targets, (b) how sex differences can affect the preclinical AEG study designs and analysis of outcome measures, and (c) what factors should be considered when examining the effect of sex on outcome of clinical AEG trials or the clinical use of AEGs.