The assessment of patients with refractory epilepsy presents both a challenge and an opportunity. The use of appropriate instruments to carefully and consistently measure a patient's seizure type and frequency, hormonal function, and medication side effects and the impact of those variables on quality of life ensures consistent, standardized assessment. A patient's epilepsy then can be classified as refractory based on any combination of factors that preclude a reasonably normal life-style by current practice standards, given the person's capabilities. Diagnostic studies and treatment strategies should address all significant adverse findings resulting from the assessment process. Accurate diagnosis of seizure type usually requires electroencephalographic (EEG) monitoring. Postictal hormonal assays and periodic measurements of estrogen and progesterone may be useful diagnostically in a selected group of patients. Awareness of a patient's compliance history, environmental stressors, and seizure triggers may reduce seizure frequency without a change in medication. For patients with medication intolerance, the usual strategy is to modify the medication regimen or treatment schedule to minimize side effects while maximizing seizure control and compliance. For most patients, monotherapy provides a greater therapeutic window than combination therapy. Devising an effective and safe therapeutic regimen is an ongoing process and can be lengthy depending on seizure type(s), frequency, and temporal pattern; anticonvulsant pharmacokinetics; drug interactions and side effects; patient's life-style; and other factors. Serial measurements of quality-of-life variables may assist in the process. Rapid strides have been recently made, and as the pace of new antiepileptic drug development quickens and surgical centers become more widely available, clinicians will need to redefine refractoriness as the expectations improve for patients with epilepsy.