Temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) commonly arise following early-life long seizures, and especially febrile status epilepticus (FSE). However, there are major gaps in our knowledge regarding the causal relationships of FSE, TLE, HS and cognitive disturbances that hamper diagnosis, biomarker development and prevention. The critical questions include: What is the true probability of developing TLE after FSE? Are there predictive markers for those at risk? A fundamental question is whether FSE is simply a marker of individuals who are destined to develop TLE, or if FSE contributes to the risk of developing TLE. If FSE does contribute to epileptogenesis, then does this happen only in the setting of a predisposed brain? These questions are addressed within this review, using information gleaned over the past two decades from clinical studies as well as animal models.