Lyme neuroborreliosis has a protean clinical spectrum and a complex and still obscure pathogenesis. Central and peripheral nervous system involvement may occur, with several different mechanisms acting together or separately. Invasion of the nervous system by Borrelia burgdorferi occurs early in the course of the infection. Direct interaction of the spirochete with neural cells may result in neurological damage, as may the immune response elicited against the organism. Both T- and B-cell autoreactivity against endogenous neural structures is present and there seems to be a crossreaction between neural antigens and the flagellin of Borrelia burgdorferi. Meningitis is probably due, at least in part, to inflammatory mechanisms elicited by the presence of spirochetes in the CSF. Inflammatory and angiopathic peripheral nerve changes may lead to axonal damage resulting in peripheral neuropathy. The elaboration of proinflammatory mediators provides another possible pathway for nerve cell injury. There is still a lack of a suitable animal model to recreate the neurological manifestations paralleling human disease. However, rat and mouse models and, more recently, nonhuman primates have so far provided important information on the pathogenesis of this infection and hopefully will provide the opportunity to elucidate many still unclear mechanisms.