Preclinical studies have produced numerous drugs with antiseizure properties which currently are the standard of care in clinical care. A third of the human population with epilepsy still continues having seizures despite the ongoing discoveries. The recognized clinical gaps of care that need to be addressed are the identification of antiepileptogenic and disease modifying treatments, treatments for refractory seizures or for seizures and epilepsies with limited or unsatisfactory treatments, such as early life epileptic encephalopathies. In this invited review, we provide a historical summary of the international efforts to re-evaluate the strategies adopted in preclinical epilepsy therapy discovery studies. We discuss issues that may impact the quality, interpretation and validation of preclinical studies and their translation to successful therapies for humans affected with epilepsy. These include the selection of animal models and the study design, research practices that affect rigor, such as appropriate use of statistics and reporting of study methods and results, their validation across models, labs and preclinical-clinical studies, the need to harmonize research methods and outcome assessment, and the importance to improve translation to clinically appropriate situations. The epilepsy research community is incrementally adopting collaborative research, including consortia or multicenter studies to meet these needs. Improving the infrastructure that can support these efforts will be instrumental in the future success.