Epilepsy is increasingly recognized as a disease that reaches well beyond seizures. Cognitive and psychiatric impairment affect half of all epilepsy patients, and to date there are no specific treatments for these symptoms. It is unclear which of these comorbidities are directly due to seizures and which are due to separable mechanisms that are parallel to those underlying ictal activity. Cellular and molecular mechanisms underlying synaptic modulation are central to both the ictal and nonictal changes in epilepsy. Current diagnostic methods are rapidly advancing to better delineate the nature and extent of ictal activity, and could soon be critical in identifying patterns unique to the cognitive and psychiatric comorbidities.