Most patients reporting more than one well-documented or witnessed seizure require prophylactic antiepileptic (AED) therapy. Those with an underlying brain disorder and/or an abnormal electroencephalogram should probably be treated after their first event. The goal should be maintenance of a normal lifestyle by complete seizure control with no or minimal side-effects. Failure of the first AED due to lack of efficacy implies refractoriness. A policy of consecutive substitutions is unlikely to be an effective strategy. Thus, if the first or second monotherapy improves control but does not produce seizure freedom, an AED with different and perhaps multiple mechanisms of action should be added. Strategies for combining drugs should involve individual assessment of patient-related factors, including seizure type and epilepsy syndrome classifications coupled with an understanding of the pharmacology, side-effects and interaction profile of the AEDs. Reducing the dose of one or more AEDs may help accommodate the introduction of a second or third drug. An orderly approach to the pharmacological management and, when appropriate, surgical investigations for each epilepsy syndrome will optimise the chance of perfect seizure control and help more people achieve safer and more fulfilled lives.