Approximately one third of all epilepsy patients are resistant to current therapeutic treatments. Some patients with focal forms of epilepsy benefit from invasive surgical approaches that can lead to large surgical resections of human epileptic neocortex. We have developed a systems biology approach to take full advantage of these resections and the brain tissues they generate as a means to understand underlying mechanisms of neocortical epilepsy and to identify novel biomarkers and therapeutic targets. In this review, we will describe our unique approach that has led to the development of a 'NeuroRepository' of electrically-mapped epileptic tissues and associated data. This 'Big Data' approach links quantitative measures of ictal and interictal activities corresponding to a specific intracranial electrode to clinical, imaging, histological, genomic, proteomic, and metabolomic measures. This highly characterized data and tissue bank has given us an extraordinary opportunity to explore the underlying electrical, cellular, and molecular mechanisms of the human epileptic brain. We describe specific examples of how an experimental design that compares multiple cortical regions with different electrical activities has led to discoveries of layer-specific pathways and how these can be 'reverse translated' from animal models back to humans in the form of new biomarkers and therapeutic targets.