The acute aseptic meningitis syndrome is an entity that presents a diagnostic challenge to the clinician. Although many infectious and noninfectious etiologies exist for this syndrome, viruses, especially nonpolio enteroviruses, are the classic and most important agents encountered. The incidence of polio and mumps meningitis has declined dramatically in the vaccine era, but recently described pathogens, such as human immunodeficiency virus and Borrelia burgdorferi (Lyme disease agent) are now important considerations in the differential diagnosis. Specifically treatable entities (eg, mycobacterial or fungal meningitis, herpes simplex encephalitis, parameningeal infection) that may mimic aseptic meningitis in their initial presentations must not be overlooked. A careful approach to the patient and a rational use of laboratory studies are the basis for establishing a specific diagnosis and assuring a favorable outcome.