Recent advances in our understanding of the fundamental mechanisms of epilepsy have derived, to a large extent, from improvements in designing parallel human and animal studies. This is the result not only of better animal models of human epileptic phenomena, but of an increasing ability to carry out detailed invasive studies on patients in the course of surgical treatment for medically refractory epilepsy. In addition to interictal and ictal video-EEG recordings with chronic depth and subdural electrodes, it is also possible to sample single-unit activity with chronically implanted microelectrodes, and measure constituents of extracellular fluid with chronically implanted microdialysis probes, using protocols that in the past were possible only in the experimental animal laboratory. Subsequent surgical resection provides tissue that can be used for electrophysiological, morphological, biochemical, and molecular biological investigations. Patients in epilepsy surgery facilities represent a precious resource for research that should be utilized to the fullest extent possible by basic scientists interested in mechanisms of epilepsy. It is particularly important that invasive research be pursued now, because improved diagnostic technology is greatly reducing the need for chronic intracranial electrode recordings, and surgical approaches that do not yield tissue could be used more commonly in the future. Therefore, the capacity to carry out invasive research in the context of epilepsy surgery may diminish greatly over time. To take full advantage of these opportunities, carefully designed iterative experimental protocols are necessary to characterize abnormalities in the human epileptic brain, to create appropriate experimental animal models to study these phenomena in greater detail, and to return to the human brain to validate the clinical relevance of observations made on animals. It is also important, however, to recognize certain unavoidable limitations of human research, including ethical considerations, variability inherent in the clinical setting, imprecision in defining target areas, lack of control data, and small subject numbers, which continue to make animal investigations essential to the achievement of our goals of defining fundamental mechanisms of human epileptic phenomena.