Diagnosis of HSV CNS disease in the PCR era is much less invasive than in prior decades. Nothing as yet, however, usurps the judgment of the clinician as she or he cares for their patient. False negative (and false positive) CSF PCR results are well documented in the literature. If the physician's clinical suspicion is of HSV disease of the CNS, the management course should not be diverted solely on the basis of 1 negative HSV CSF PCR result. Although the technologic achievement represented by PCR is phenomenal, the art of medicine must always prevail over simply the science of medicine. Evaluation of CSF for HSV DNA is beneficial in ruling in HSV CNS disease, but it provides no information regarding HSV disease elsewhere in the body. Given that approximately one-half of infants with neonatal HSV do not have CNS involvement (either SEM disease or disseminated disease without CNS involvement), the diagnostic evaluation of an infant with suspected HSV disease must also include HSV cultures of skin and mucosal sites. Liver transaminases should be obtained, because their elevation could suggest disseminated HSV infection involving the liver. Other diagnostic modalities on which the clinician can also base his or her diagnostic and therapeutic decisions regarding the likelihood of HSV CNS infection include EEGs and neuroimaging studies such as CT and MRI. Neither CT nor EEG is very sensitive, and EEG is the least specific of these modalities. On the other hand, MRI findings have a high degree of correlation with HSV PCR results from CSF. Copyright © 2006 by Lippincott Williams & Wilkins.