Epilepsy refers to a cluster of neurological diseases characterized by seizures. Although many forms of epilepsy have a well-defined immune etiology, in other forms of epilepsy an altered immune response is only suspected. In general, the hypothesis that inflammation contributes to seizures is supported by experimental results. Additionally, antiepileptic maneuvers may act as immunomodulators and anti-inflammatory therapies can treat seizures. Triggers of seizure include a bidirectional communication between the nervous system and organs of immunity. Thus, a crucial cellular interface protecting from immunological seizures is the blood–brain barrier (BBB). Here, we summarize recent advances in the understanding and treatment of epileptic seizures that derive from a non-neurocentric viewpoint and suggest key avenues for future research.