Lyme disease is a multisystem disease caused by the spirochete Borrelia burgdorferi and is transmitted to humans primarily through Ixodid ticks. The clinical spectrum of the disease is continuing to expand while in its wake the pathology and histopathologic manifestations are being uncovered. We review the pathology of Lyme disease in man beginning with the tick bite. We present the pathologic changes of the rash, erythema migrans, as well as the neurologic, cardiac, and arthritic changes of the disease. We can expand our understanding of the immunobiology of Lyme disease by studying the interactions of B. burgdorferi in an experimental animal model.