Closed-loop brain stimulation is one of the few treatments available for patients who are ineligible for traditional surgical resection of the epileptogenic zone, due to having generalized epilepsy, multifocal epilepsy, or focal epilepsy localized to an eloquent brain region. Due to its clinical efficacy and potential to delivery personalized therapy based on an individual's own intracerebral electrophysiology, this treatment is becoming an important part of clinical practice, despite a limited understanding of how to program detection and stimulation parameters for optimal, patient-specific benefit. To bring this challenge into focus, we review the evolution of neural stimulation for epilepsy, provide a technical overview of the RNS System (the only FDA-approved closed-loop device), and discuss the major challenges of working with a closed-loop device. We then propose an evidence-based solution for individualizing therapy that is driven by a bottom-up informatics approach.