Epilepsy comprises a group of disorders characterized by the periodic occurrence of seizures. Currently available anticonvulsant drugs and therapies are insufficient to control seizure activity in about one-third of patients with epilepsy. Thus, there is an urgent need for new therapies that prevent the genesis of the disorder and improve seizure control in individuals already afflicted. The vast majority of epileptic cases are of idiopathic origin, and a deeper understanding of the cellular basis of hyperactivity and synchronization is essential. Neurosurgical specimens from patients presenting with temporal lobe epilepsy (TLE) typically demonstrate marked reactive gliosis. As recent studies have implicated astrocytes in important physiological roles in the CNS, such as synchronization of neuronal firing, it is plausible they may also have a role in seizure generation and/or seizure spread. In support of this view, several membrane channels, receptors, and transporters in astroglial membranes have been found to be deeply altered in the epileptic brain. Excitingly, recent evidence suggests that in the course of the pathogenesis of TLE, these glial changes alter homeostatic network functions and temporally precede the alterations in neurons. These findings might eventually classify TLE as a glial rather than a neuronal disorder, and identify glial cells as promising new targets for the development of more specific antiepileptic therapeutic strategies. In this Special Issue, we have compiled a series of review articles that summarize current evidence of astrocyte dysfunction in epilepsy and discuss presumed underlying mechanisms and evolving therapies. Although research on glial cells in epilepsy is still in its infancy, these reviews clearly demonstrate a critical role of astrocytes in the disturbance of K+ and transmitter homeostasis and its impact on seizure generation. We like to thank all authors for their valuable contributions and hope that this Special Issue helps to foster the search for alternative approaches to cure epilepsy.