Human herpes virus 6 (HHV6) infection is nearly ubiquitous in childhood and may include central nervous system invasion. There are two variants, HHV6A and HHV6B. Usually asymptomatic, it is associated with the common, self-limited childhood illness roseola infantum and rarely with more severe syndromes. In patients with immune compromise, subsequent reactivation of viral activity may lead to severe limbic encephalitis. HHV6 has been identified as a possible etiologic agent in multiple sclerosis, myocarditis, and encephalitis. A preponderance of evidence supports an association between HHV6 and febrile seizures. An ongoing multicenter study is investigating possible links between HHV6 infection, febrile status epilepticus, and development of mesial temporal sclerosis (MTS). Investigation of temporal lobectomy specimens showed evidence of active HHV6B but not HHV6A replication in hippocampal astrocytes in about two-thirds of patients with MTS but not other causes of epilepsy. It has been suggested that HHV6B may cause "excitotoxicity" by interfering with astrocyte excitatory amino acid transport. Although conventional inflammatory changes are not found in most MTS specimens, inflammatory modulators may play a role in neuronal injury leading to MTS as well. If the link between early viral infection, complex or prolonged febrile seizures, and later development of intractable temporal lobe epilepsy is confirmed, new therapeutic approaches to a common intractable epilepsy syndrome may be possible.