- Postinjury epilepsy (PIE) is a devastating sequela of insults to the brain, such as traumatic brain injury (TBI), stroke, and infection. Following a latent period that may last months to years after the injury (i.e epileptogenesis), up to 40% of survivors may develop epilepsy and suffer from recurrent seizures. To date there are no means to identify patients at risk to develop epilepsy after an insult or to prevent the development of this disorder. The blood–brain barrier (BBB) is a specialized interface formed collectively in the central nervous system (CNS). Its highly selective permeability mainly due to tight junction proteins and specific transporter systems makes it a key homeostasis regulator of the brain milieu. BBB disruption (BBBD) was often documented in patients and animals following various brain injuries, it is frequently observed in PIE patients and reported in various animal models of the disease. Sites of disruption frequently overlap with regions of focal abnormal electrical activity depicted using electroencephalography (EEG). These findings suggest that microvascular pathology and related BBBD may underlie epileptogenesis, and therefore have facilitated the development of animal models of BBBD. These models include: (1) Direct focal BBBD using cortical exposure to bile slats or serum-derived albumin using the open window technique; and (2) Simulation of BBB disrupted environment by using intracerebroventricular (ICV) infusion of serum components or the downstream derivatives of the activated cascades. Both approaches result in electrographic seizures in the majority of treated animals with a latent period shorter than 2 weeks, allowing research on epileptogenic mechanisms under BBBD and the testing of potential antiepileptogenic strategies.