Lyme disease represents a growing public health threat. The controversial science and politics of Lyme disease have created barriers to reliable diagnosis and effective treatment of this protean illness. Two major clinical hurdles are the absence of a therapeutic end point in treating Borrelia burgdorferi, the spirochetal agent of Lyme disease, and the presence of tickborne coinfections with organisms such as Babesia, Anaplasma, Ehrlichia and Bartonella that may complicate the course of the disease. From a pathophysiologic standpoint, the affinity of Borrelia burgdorferi for multiple cell types and the presence of nonreplicating forms of the Lyme disease spirochete have contributed to persistent infection and failure of simple antibiotic regimens. Newer approaches to the treatment of Lyme disease should take into account its clinical complexity in coinfected patients and the possible need for prolonged combination therapy in patients with persistent symptoms of this potentially debilitating illness. The optimal antibiotic regimen for chronic Lyme disease remains to be determined.