Lyme disease is of interest to the neurologist and neuroscientist for a variety of reasons. As more arthropod hosts throughout the world are infected with the causative organism, Borrelia burgdorferi, the illness in humans is becoming more prevalent; in addition, recognition of the disease in humans and susceptible animals is increasing. The neurological manifestations include acute and chronic forms, and it has become clear that B. burgdorferi has joined Treponema pallidum, herpes simplex virus, and human immunodeficiency virus (HIV) as an agent of persistent infection of the brain. Recent strides in the understanding of antigenic variation in Borrelia have provided insights into how this agent may survive in the human host. Preliminary work in animal models has provided information about the relationships between strain-dependent tropisms, spirochetemia, the development of specific antibody, and nervous system invasion. Finally, the history of the development of understanding of the disease has been a fascinating mixture of parental concern, serendipitous discovery, and correlation of clinical syndromes and serological evaluations across continents.