Until a decade ago, epilepsy research had focused mainly on alterations of neuronal activities and excitability. Such neurocentric emphasis has neglected the role of glia and involvement of inflammation in the pathogenesis of epilepsy. It is becoming clear that immune and inflammatory reactions do occur in the brain despite the brain’s lack of conventional lymphatic drainage and graft acceptance and the presence of vascular brain barrier that tightly regulates infiltration of blood monocytes and lymphocytes. The critical roles of brain-resident immune mediators and of brain-infiltrating peripheral leukocytes are increasingly recognized. Inflammatory processes, including activation of microglia and astrocytes and production of proinflammatory cytokines and related molecules, occur in human epilepsy as well as in experimental models of epilepsy. Immune mechanism that underlies evolution of drug-resistant epilepsy and epileptic encephalopathy represents a new target and will aid in development of novel immunotherapeutic drugs and therapies against the key constituents in immune pathways.