After being regarded as a last resort for over two decades, the role of combination therapy as a treatment strategy for epilepsy is undergoing reevaluation. This is a result of the growing appreciation that all seizures cannot be controlled by monotherapy in a substantial proportion of patients, and of the development of a range of modern antiepileptic drugs (AEDs), some of which are better tolerated and less prone to complex pharmacokinetic drug interactions than their older counterparts. Robust evidence to guide clinicians on when and how to combine AEDs is lacking, and current practice recommendations are largely empirical. Monotherapy should remain the treatment of choice for newly diagnosed epilepsy. A combination of two AEDs can be considered after failure, resulting from lack of efficacy, of one or two different monotherapy regimens. A few patients will become seizure-free with a combination of three AEDs, but treatment with a combination of four or more is unlikely to be successful. There is some evidence to support a pharmacomechanistic approach to AED combination. Care should be taken to avoid excessive drug load, which is associated with increased toxicity. Bigger and better randomised, controlled studies are needed to determine the optimal time and way to combine AEDs.