Herpes simplex virus (HSV) infections of the central nervous system (CNS) have varied presentations. Some, such as encephalitis, can have devastating outcomes. In only a few short decades a vast amount of knowledge has been uncovered about the pathogenicity of this virus, its diagnosis, and treatment. Non-invasive diagnostics with polymerase chain reaction have replaced brain biopsy as the mainstay of diagnosis and antiviral therapy with acyclovir has largely improved mortality. However, despite these scientific advancements, morbidity remains high. The clinician must maintain a high index of suspicion with neonates, children, and adults, as HSV can often mimic other CNS diseases and prompt initiation of treatment is integral. © 2014 Elsevier B.V.