The natural history of treated epilepsy has substantial relevance to its pharmacologic and surgical management. In our center, 525 unselected, untreated patients were given a diagnosis of epilepsy, started on antiepileptic drug (AED) therapy, and followed for a median of 5 years. Sixty-three percent of patients had been seizure-free for at least the previous year. Forty-seven percent of 470 previously drug-naïve patients responded to their first AED. Thirteen percent were seizure-free on the second AED, and 1% on the third monotherapy choice. Only 3% were controlled with two AEDs and none with three. The prognosis for patients whose epilepsy did not respond to the first AED was strongly associated with the reason for failure. Only 11% of patients with inadequate control on the first AED later became seizure-free. These results suggest that patients with newly diagnosed epilepsy comprise two distinct populations. Around 60% will be controlled on monotherapy, usually with the first or second AED chosen. The remaining 30 to 40% will be difficult to control from the outset. A management plan should be formulated for each patient when treatment is started. Strategies for combining drugs should involve individual assessment of patient-related factors, including seizure type and epilepsy syndrome classification, combined with an understanding of the mechanisms of action, side effects, and interactions of the AEDs. Epilepsy surgery should be considered after failure of two well-tolerated treatment regimens, whether as monotherapy or with one monotherapy and the first combination. Prevention of refractory epilepsy should be the goal of treatment when the first AED is prescribed. A staged approach to the pharmacologic management and, when appropriate, surgical work-up for each epilepsy syndrome will optimize the chance of perfect seizure control and help more patients achieve a fulfilling life.