Epilepsy is a chronic neurological disorder characterized by the rapid occurrence of epileptic seizures affecting approximately 70 million people worldwide. The quality of life of people with epilepsy (PWE) is challenged by a series of comorbidities that might include neurologic and neuropsychiatric disorders (cognitive decline, depression, anxiety, schizophrenia, and autism) as well as metabolic, cardiovascular and respiratory diseases. Neurobehavioral and other comorbidities might share a reciprocal and complex relationship with epileptogenesis and ictogenesis thus biomarkers of the former might be useful for the prediction of the latter and vice versa. This bidirectional relationship between epilepsy and associated comorbidities has attracted significant attention in recent years as supported by data showing that one half of PWE demonstrate cognitive impairments, 30-50% depressive behavior, 10-25% anxiety disorders and 5-40% autism or autism spectrum disorder (ASD). In the past decades, epilepsy-related neurobehavioral comorbidities have been critically discussed, but the current need in unraveling the precise mechanism associated with epilepsy and these neurobehavioral comorbidities is unmet. The precise understanding of the mechanistic pathway underlying these epilepsy-associated comorbid conditions could be instrumental in developing therapeutic interventions that might modify seizure burden and accompanying comorbid conditions.