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Central nervous system invasion by Treponema pallidum, the causative agent of syphilis, occurs in many, if not most, patients with syphilis. Laboratory findings from untreated asymptomatic syphilis patients with abnormalities of cerebrospinal fluid are termed asymptomatic neurosyphilis and represent a group that has an increased risk for developing clinical neurosyphilis syndromes. Clinical neurosyphilis syndromes, which occur in a minority of patients, may become apparent at any time in the natural history of untreated disease and often cause serious morbidity for individuals who develop them. Because there is no single sensitive and highly specific test for neurosyphilis diagnosis, clinicians must approach this important syndrome using a combination of clinical and laboratory data and a firm understanding of the disease.