Syphilis is a bacterial infection caused by Treponema pallidum subspecies pallidum (hereafter T. pallidum) which causes approximately 6 million new infections annually worldwide. It is relevant to neurologists because T. pallidum can invade the central nervous system and cause neurosyphilis. Neurosyphilis can occur at any time after primary infection. In early syphilis, neurosyphilis can be asymptomatic or can present with meningitis, stroke, and/or cranial neuropathies. In late syphilis, neurosyphilis typically presents as dementia or sensory ataxia. The exact prevalence of neurosyphilis is largely unknown worldwide, but neurosyphilis has become more common in the setting of the HIV epidemic as individuals with HIV and syphilis co-infection seem to develop neurosyphilis at higher rates than HIV-uninfected individuals. Diagnosis of neurosyphilis requires serological evidence of syphilis and compatible cerebrospinal fluid (CSF) abnormalities. The diagnosis is not straightforward as the CSF Venereal Disease Research Laboratory (VDRL) test, the gold standard diagnostic test for neurosyphilis, is only 30–70% sensitive. Treatment for neurosyphilis involves 10–14 days of high-dose penicillin, and treatment for uncomplicated syphilis will not adequately treat most cases of neurosyphilis. The pathophysiology of neurosyphilis involves humoral immune responses, at least partially driven by CXCL-13 mechanisms. However, why some individuals with syphilis develop neurosyphilis and others do not is incompletely understood but likely relates to both pathogen factors (i.e. strain type) and host factors (e.g. polymorphisms in genes regulating immune response to the infection and host immune status).