Lyme disease, the multisystem infectious disease caused by the tick-borne spirochete Borrelia burgdorferi involves the nervous system in 10-15% of affected individuals. Manifestations include lymphocytic meningitis, cranial neuritis, radiculoneuritis, and mononeuropathy multiplex. Encephalopathy, identical to that seen in many systemic inflammatory diseases, can occur during active systemic infection. It is not specific to Lyme disease and only rarely is evidence of nervous system infection. Diagnosis of systemic disease is based on demonstration of specific antibodies in peripheral blood by means of two-tier testing with an ELISA and Western blot. Central nervous system infection often results in specific antibody production in the CSF, demonstrable by comparing spinal fluid to blood serologies. Treatment is straightforward and curative in most instances. Many patients can be treated effectively with oral antibiotics such as doxycycline; in severe CNS infection parenteral treatment with ceftriaxone or other similar agents is highly effective. Treatment should usually be for 2 to at most 4 weeks. Longer treatment adds no therapeutic benefit but does add substantial risk.