Diagnosis of complex partial epilepsy is based on the clinical history, and laboratory tests, including EEG and neuroimaging studies, corroborate the diagnosis. The goal of epilepsy management is to make the patient completely seizure-free without drug-induced side effects, even in the patient with refractory complex partial seizures. Frequently this can be accomplished by choice of the optimal antiepileptic drug (AED) or a combination of drugs, the use of strategies to maximize the effectiveness of drug treatment, or by surgical removal of the seizure focus. Currently there are five “classical” first-line AEDs and 11 new AEDs available in the US and in many other countries for the treatment of localization-related epilepsy. The current state of the evidence is that no AED is clearly superior to other AEDs in the management of refractory complex partial seizures. Therefore the choice of which drug to use in an individual patient has to be based on other considerations, including the potential adverse reactions that may occur in that patient. There are a number of strategies for optimal use of AEDs in the management of refractory complex partial seizures. These include verification of the diagnosis of epilepsy and classification of specific seizure types, use of monotherapy if possible but polytherapy if necessary, starting with a low dose and raising it slowly but, until complete seizure control is achieved, pushing to the maximum tolerated dose, changing timing of dosing to reduce toxicity, using pharmacokinetic principles to fine-tune AED doses, adjusting dose for drug–drug interactions, and never giving up in the pursuit of better seizure control. Resection of the seizure focus can be curative in the majority of patients with seizures localized to one mesial temporal lobe. Success rates for resection of extratemporal seizure foci are lower. Vagus nerve stimulation (VNS) devices result in a significant reduction of seizure frequency in many patients, but patients rarely become completely seizure-free as a result of VNS device implantation. Management of refractory complex partial seizures continues to improve with the identification of new drugs and the development of new approaches to their control and cure