Summary: Many different types of epileptic seizures and epileptic syndromes exist. The process of epileptogenesis and the progressive nature of epilepsy, however, can most easily be investigated in the acquired epilepsies, in which a brain insult presumably gives rise to changes in neuronal systems that ultimately become capable of generating spontaneous ictal events. Invasive in vivo and in vitro research can be carried out in patients with acquired epileptogenic lesions in the course of epilepsy surgery; however, such studies are possible only for those epileptic conditions that can be treated surgically, and can be used only to examine an end stage of the epileptogenic process. Consequently, experimental animal models of human epileptic conditions are still required to study mechanisms by which specific cerebral insults initiate the epileptogenic process and the progression of an epileptic disturbance. Most current parallel human/animal invasive research has been focused on temporal lobe epilepsy, and particularly that form associated with hippocampal sclerosis, the most common human epileptogenic lesion. Studies indicate that epileptogenesis in this condition is initiated by specific types of cell loss and neuronal reorganization, which results not only in enhanced excitation, but also in enhanced inhibition, predisposing to hypersynchronization. Even within this single, well-studied epileptic disorder, evidence is found for more than one type of ictal onset, and individual seizures can demonstrate a transition from one ictal mechanism to another. Recent in vivo and in vitro parallel, reiterative investigations in patients with mesial temporal lobe epilepsy, and in rats with intrahippocampal kainate-induced hippocampal seizures, have revealed the presence of interictal epileptiform events, termed “fast ripples,” which appear to be unique in tissue capable of generating spontaneous seizures. Pursuit of the fundamental mechanisms underlying these abnormalities should elucidate the neurobiologic basis of epileptogenicity in this disorder. Furthermore, if these events are markers for epileptogenicity, they may have clinical value for diagnosis and pharmacologic, as well as surgical, treatment. Further research is needed to determine if these observations are relevant to other types of epilepsies.