Experimental evidence and pathological observation indicate that human cytomegalovirus (HCMV) has a tropism for cells of the nervous system, including both neuronal and glial cells. As demonstrated in animal models, after a viremic phase, the virus may reach the brain, where it may cause mild infection or severe encephalitis. The nervous system is one of the principal target organs in congenital HCMV infections and in HCMV-infected AIDS patients. In the former case, mortality is high and neurological sequelae, such as mental retardation, are frequent; in the latter it may lead to a progressively wasting encephalopathy and death within a few weeks. The diagnosis of the nervous system manifestations due to HCMV can now rely upon the detection of HCMV DNA in cerebrospinal fluid by means of polymerase chain reaction. However, the current antiviral treatments of these complications are of limited effect.