In focal epilepsy, seizures are generated by a localized, synchronous neuronal electrical discharge that may spread to large portions of the brain. In spite of intense research in the field of epilepsy, a key question remains unanswered: what are the earliest cellular events leading to the initiation of a focal seizure? Elucidating this issue is of paramount importance both for understanding the pathophysiology of focal epilepsies and for the development of new pharmacological strategies for drug-resistant forms of these disorders.