Lyme disease is the most common tick-borne disease in the world today. Despite extensive research into the complex nature of Borrelia burgdorferi, the spirochetal agent of Lyme disease, controversy continues over the diagnosis and treatment of this protean illness. This report will focus on two aspects of the treatment of Lyme disease. First, the medical basis for diagnostic and therapeutic uncertainty in Lyme disease, including variability in clinical presentation, shortcomings in laboratory testing procedures, and design defects in therapeutic trials. Second, the standard of care and legal issues that have resulted from the clinical uncertainty of Lyme disease diagnosis and treatment. Specifically, the divergent therapeutic standards for Lyme disease are addressed, and the difficult process of creating treatment guidelines for this complex infection is explored. Consideration by healthcare providers of the medicolegal issues outlined in this review will support a more rational approach to the diagnosis and treatment of Lyme disease and related tick-borne illnesses.