There are several different types of comorbidities exist in epilepsy. Cognitive comorbidities are learning problems that cause difficulty in school and can have lasting effects on educational and professional success;Psychiatric comorbidities are behavior and mood problems including attention deficit disorder, depression, anxiety disorders and combinations of these conditions. Comorbidities in epilepsy impair patients’ health-related quality of life and may affect the clinical course of epilepsy. Comorbidities and epilepsy have a bidirectional relationship, sharing common underlying pathogenesis. This special issue updated readers with some of the most recent and exciting progresses including mechanisms, evaluation biochemical biomarkers for epilepsy and comorbidities as well as therapy aim to modify the progression of epilepsy (disease modification) and concomitant comorbidities through by targeting the disease process. It is hoped that such advances in cognitive neuroscience and psychiatry will translate into routine epilepsy clinical practice and provide markers of disease and more targeted treatments. The potential limitations and future efforts with open questions were also offered to stimulate the further research endeavors in the field.