Pharmacotherapy of epilepsy is usually initiated after two or more unprovoked seizures, a decision that should be made after assessment of the individual risk of further seizures. Antiepileptic drugs (AEDs) are selected based on documented efficacy for the type of seizures, the epilepsy and possible epilepsy syndrome of the patient, taking potential adverse effects and comorbidity into account. For many AEDs, the mechanisms of action are incompletely understood. More than half of patients with newly diagnosed epilepsy achieve sustained seizure freedom with their first or second drug trials. After a prolonged time of seizure freedom discontinuation of therapy may be considered; the risk of relapse after drug withdrawal can be estimated on the basis of a number of clinical factors. The informed patient’s attitude is essential in all therapy decisions. Treatment is still largely symptomatic, but the future may involve a greater degree of disease-modifying precision medicine.