Herpes simplex virus type 1 (HSV-1) is ubiquitous, neurotropic, and the most common pathogenic cause of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequels. HSV-1 infects limbic system structures in the central nervous system (CNS), and has been suggested as an environmental risk factor for Alzheimer's disease. The possibility that HSV-1 reactivates in CNS neurons causing chronic progressive damage at cellular level and altering the neuronal functionality has not been thoroughly investigated. Currently it is ignored if recurrent reactivation of HSV-1 in asymptomatic patients involves some risk of progressive deterioration of the CNS functions caused, in example, by a neuroinflammatory response against the virus or by direct toxicity of the pathogen on neurons. Therefore, studies regarding the routes of dissemination of HSV-1 from the peripheral ganglions to the CNS, as well as the possible cellular and molecular mechanisms implied in generating neuronal damage during latent and productive infection, are of much relevance.