Beginning in the 1970s engineers designed systems to predict epileptic seizures based upon quantitative changes in the electroencephalogram, which they hypothesized began well in advance of clinical seizure onset. These efforts flourished in the 1990s, as independent laboratories demonstrated evidence of a ‘preseizure period’ up to 20 min prior to clinical symptoms in patients implanted with intracranial electrodes during evaluation for epilepsy surgery. Years later, clinical and laboratory experiments leave little doubt that a preseizure period exists in temporal lobe and perhaps other forms of epilepsy. Its existence, however, raises fundamental questions about what constitutes a seizure, what brain regions are involved in seizure generation, and whether discrete interictal, preictal, ictal and post-ictal physiologies exist, or blend together in a continuous process. Pressing milestones, necessary for clinical utility, are: (1) demonstrating prospective seizure prediction from prolonged human data sets, (2) elucidating mechanisms underlying seizure precursors and (3) implementing these algorithms on implantable hardware platforms. The notion of a preseizure state is catalyzing new clinical and basic science research, which has the potential to dramatically increase our understanding of epilepsy, and to generate exciting new therapies for patients.