Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system early in the course of disease but causes persistent infection in only a subset of infected persons. Individuals with persistent infection or asymptomatic meningitis are at risk for developing symptomatic neurosyphilis if they are not treated with a drug regimen that achieves sufficient drug levels in cerebrospinal fluid to kill the organism. In this article, recent studies that address the risk, diagnosis, and management of neurosyphilis are discussed within the context of a brief review. Particular attention is given to current controversies. In the developed world, these issues are particularly relevant to persons who are infected with HIV.