Lyme disease is a multisystem disorder caused by infection with the Borrelia burgdorferi spirochete. The diagnosis of Lyme disease usually is based on several clinical criteria, with supportive data from laboratory testing. The presence of the bullseye skin lesion, erythema migrans, is the single pathognomonic criterion. In the 20 years since the initial description of Lyme disease in the United States, B. burgdorferi has been implicated as an etiologic agent in numerous ophthalmic and neuro-ophthalmic syndromes, involving most structures from the cornea to the cranial nerves. Neuro-ophthalmic and ocular manifestations of Lyme disease include meningitis with papilledema, cranial neuropathies, follicular conjunctivitis, nummular keratitis, and intraocular inflammation. Although an association with Lyme disease has been purported for numerous other syndromes, a definite causal relationship has not been proved in many cases. During a period of rapidly increasing awareness of Lyme disease, a high index of suspicion and poorly defined criteria for its presence have resulted in over-diagnosis of Lyme disease. In the authors' experience, the incorrect diagnosis of Lyme disease initially has been made in patients with allergic conjunctivitis, keratoconus, morning glory syndrome, craniopharyngioma, meningioma, CNS lymphoma, paraneoplastic syndrome, multiple sclerosis, sarcoid, syphilis, and functional illness. Nevertheless, this treatable infection must be an important consideration in the differential diagnosis of certain ocular or neurologic diseases.