Summary: Mesial temporal sclerosis (MTS) is found in about two-thirds of patients with refractory temporal lobe epilepsy (TLE), and surgical removal of the sclerotic structures eliminates seizures in the majority of cases undergoing surgical resection. Although multiple factors have been implicated in the genesis of MTS, it is still unclear why some individuals are more likely to develop hippocampal sclerosis than others. Epileptologists have proposed that there must be at least two factors involved—an initial precipitating injury (IPI), such as a prolonged febrile seizure, CNS infection, or head trauma, and a second factor that increases vulnerability to neuronal injury. This has been termed the “two-hit hypothesis.” Three of the many factors that could possibly heighten susceptibility to neuronal injury and MTS are discussed here. These are microdysgenesis, hippocampal dysgenesis, prior seizures, and genetic predisposition. We conclude that there is currently no compelling evidence to support a role for microdysgenesis in MTS. Hippocampal dysgenesis, on the other hand, may account for febrile seizures and possibly MTS in a small subpopulation of patients with TLE. Additional larger studies are needed to confirm these findings. Experimental evidence indicates that an epileptogenic hippocampus can result from prolonged febrile seizures in infant rats, even though these seizures do not cause MTS in the rat. It is not known if this pathophysiological sequence occurs in humans. Lastly, there appears to be a strong genetic component that predisposes some individuals to MTS, regardless of whether they experience an IPI.