This paper focuses on the advances that have been made in our understanding of the pathogenesis, diagnosis, treatment, and prevention of herpes simplex virus (HSV) infections. Insights have been gained into the immune defense mechanisms that may be active in protecting the fetus from HSV infection. An animal model that closely mimics human neonatal HSV disease may permit exploration of novel interventional strategies. Brain biopsy for the diagnosis of HSV encephalitis has been supplanted by polymerase chain reaction detection of HSV DNA in the cerebrospinal fluid and, to a lesser extent, by detection of intrathecal HSV-specific antibodies. Prolonged immune activation within the nervous system following HSV encephalitis has been demonstrated and may implicate immune activation in the pathogenesis of HSV-induced neurologic damage. The continuing emergence of antiviral drug resistance further underscores the need for new strategies for treatment and prevention of HSV infections.