Cortical migration defects are often associated with epilepsy. In mesial temporal lobe epilepsy (MTLE), granule cell dispersion (GCD), a migration defect of dentate granule cells, is frequently observed. Little is known how GCD develops and to which extent it contributes to the development of seizure activity. Since the reelin-deficient reeler mouse mutant shows a similar migration defect of dentate cells, we performed a series of studies investigating whether reelin deficiency is involved in GCD development. We show that in MTLE patients and in a mouse model of MTLE, the development of GCD correlates with a loss of the extracellular matrix protein reelin. In addition, we present evidence that GCD occurs in the absence of neurogenesis, thus representing a displacement of mature neurons due to a reelin deficiency. Accordingly, antibody blockade of reelin function in naïve, adult mice induced GCD. Finally, we show that GCD formation can be prevented by infusion of exogenous reelin. In summary, these studies show that in epilepsy reelin dysfunction causes GCD development and that reelin is important for the maintenance of layered structures in the adult brain.