Treponema pallidum subspecies pallidum, the causative agent of syphilis, disseminates to the central nervous system within days after exposure. Clinical manifestations can occur during any stage of the infection, and include asymptomatic neurosyphilis, acute meningeal syphilis, meningovascular syphilis, paretic neurosyphilis, and tabetic neurosyphilis. The majority of cases are reported in HIV-infected patients but the epidemiology of modern neurosyphilis is not well defined because of the paucity of population-based data. Decreasing reports of late neurosyphilis have been countered with increasing reports of early neurologic involvement. This review summarizes the clinical manifestations, diagnosis, and therapy of neurosyphilis, focusing on areas of continued controversy, and highlighting several important questions that remain unanswered. Since 2000, the rates of syphilis continue to increase. Given the effectiveness of penicillin therapy, these trends suggest a failure of prevention. Regrettably, rather than become an infection of historical significance, syphilis in the era of HIV continues to challenge researchers and clinicians.