Recent clinical management of herpes simplex virus encephalitis (HSVE) is reviewed. The polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) has been established as a gold standard method. However, several problems for the PCR remain, as follows: the difference of minimum detection sensitivities in PCR, and pseudo-negative result which depend on the day of CSF sample collection after onset. Based on these problems, the diagnostic management of the recent guideline in USA (2008) was revised. Antiviral therapy is highly effective in reducing the mortality rate. However, only less than one-half of patients are able to return to normal. Recent therapeutic managements in EU (2007) and USA recommended acyclovir treatment for 2-3 weeks. However, according to the analysis of prolonged clinical course of HSVE (Taira N et al. 2009), such prolonged acyclovir treatment had a limited potential in their outcome. We recently reported that one pharmacological mechanism related to corticosteroid in HSVE was apparently inhibition of pro-inflammatory cytokines such as IL-6 (Kamei S et al. 2009).