Single photon emission computed tomography (SPECT) has increasingly been used as a diagnostic procedure for localizing epileptic seizure foci and as a research tool for investigating the physiologic mechanisms underlying seizure activity. With increasing use of SPECT in localizing the seizure focus for epilepsy surgery, there arises a need to critically assess its current role in the evaluation of patients for epilepsy surgery, especially as it relates to other clinical and laboratory data used in presurgical evaluation. Ictal EEG discharge has traditionally been used as the "gold standard" against which SPECT studies are compared in assessing the latter's localizing value. However, this practice presents a major challenge because SPECT studies are often reserved for patients with nonlocalizing EEG or magnetic resonance imaging findings. Nonetheless, SPECT studies in evaluation for epilepsy surgery should always be performed with the knowledge of the patient's EEG activity preceding, during, and after the injection of the radiotracer. The advent of techniques such as subtraction SPECT with co-registration on magnetic resonance imaging (SISCOM) and computer image-guided surgery has great potential in enhancing the clinical electrophysiologic evaluation of SPECT-detected abnormalities in epilepsy. These techniques permit accurate spatial correlation between intracranial EEG activity and SPECT perfusion patterns. The techniques can also be used to evaluate the effect of the extent of EEG focus resection compared with that of SISCOM focus resection to determine which has more prognostic importance in postsurgical control of seizures. Both animal and human studies are warranted to advance our knowledge of the electrophysiology associated with the various SPECT perfusion patterns.