Herpes simplex virus (HSV) infections of the central nervous system (CNS) are infrequent in occurrence, but potentially devastating in outcome. Tremendous advances in the ability to diagnose HSV CNS disease without the need for invasive procedures such as brain biopsy, coupled with the establishment of safe and effective antiviral therapies, have improved overall outcomes. However, the seriousness of HSV CNS infections requires that clinicians maintain a high index of suspicion to initiate evaluation under suitable circumstances. In addition, clinicians need an understanding of the clinical disease course in order to interpret the diagnostic tests appropriately. Intravenous aciclovir remains the mainstay of antiviral management. Even with recent treatment advances and enhanced awareness, potentially devastating outcomes remain possible.