While the main interest in the pathogenesis of herpes simplex virus (HSV) in the sixties had been focussed on acute infections, in the seventies latent infection has become the main foal of investigation. Despite of overwhelming literature, the HSV persistence has remained a continuing problem from the practical as well as theoretical points of view. Nevertheless, the following conclusions can be made: 1) HSV spreads along nerves inside as well as outside axons; 2) it resides in a non-productive form for lifelong in the sensory or vegetative ganglia; and 3) it is intermittently activated when causing peripheral virus shedding or recurrent disease. The persistence of HSV DNA in neurons may be associated with a limited transcription and translation, but the ganglia in a great majority of subjects are uninfectious during the latency period.