Only two spirochetal infections are known to cause nervous system infection and damage: neurosyphilis and neuroborreliosis (nervous system Lyme disease). Diagnosis of both generally relies on indirect tools, primarily assessment of the host immune response to the organism. Reliance on these indirect measures poses some challenges, particularly as they are imperfect measures of treatment response. Despite this, both infections are known to be readily curable with straightforward antimicrobial regimens. The challenge is that, untreated, both infections can cause progressive nervous system damage. Although this can be microbiologically cured, the threat of permanent resultant neurologic damage, often severe in neurosyphilis and usually less so in neuroborreliosis, leads to considerable concern and emphasizes the need for prevention or early and accurate diagnosis and treatment.