Herpes simplex virus (HSV) infections are among the most commonly encountered in humans. Fortunately, the resulting diseases are more usually nuisances, such as recurrent fever blisters, rather than life threatening or morbidity inducing. Nevertheless, HSV can result in disease of the central nervous system (CNS) with attendant neurological complications. Examples of the latter include herpes simplex encephalitis (HSE) or neonatal HSV infection. The past decade has witnessed significant advances in our understanding of the pathogenesis of these 2 forms of disease and, even more importantly, their amenability to treatment. This review summarises our current understanding of the natural history, pathogenesis, presentation, and treatment of HSV infections of the CNS. Because of the life-threatening nature of herpes simplex infections of the CNS, particular attention is paid to clinical presentation and differential diagnosis of confounding entities which mimic herpes simplex encephalitis. The controversy of brain biopsy versus alternative noninvasive diagnostic procedures is discussed. Clinical presentation and, importantly, the lack of uniform clinical presentation, as well as the value of intervention with appropriate antiviral drugs such as aciclovir and vidarabine (adenine arabinoside, ara-A) are stressed. The clinical outcome of herpes simplex virus infections of the CNS with therapy is particularly relevant. In spite of early intervention with selective and specific inhibitors of viral replication, return to normal function is not always achieved. At the conclusion of this review, the reader should be aware of the potential value of therapy as well as the problems encountered with diagnosis and management of patients with herpes simplex virus infections of the CNS. © 1991, Adis International Limited. All rights reserved.