Lyme disease is a controversial tick-borne illness that is estimated to be four times more common than AIDS in the United States. This paper outlines the challenges overcome in the healthcare response to human immunodeficiency virus (HIV) infection, the development of sensitive laboratory tests for the AIDS virus, and the promotion of long-term combination antimicrobial regimens to effectively treat HIV disease. We suggest that similar challenges need to be overcome before the chronic form of Lyme disease can be successfully treated. Currently, diagnosis and treatment of Lyme disease is hindered by the lack of a uniform case definition that adequately reflects the clinical presentation of the disease, poor laboratory test sensitivity, and high treatment failure rates using short-term monotherapy. Consequently the optimal treatment for patients with persistent symptoms of Lyme disease remains undefined. Although antibiotic monotherapy has been successful in treating early Lyme disease, the use of combination antibiotic therapy modelled on HIV treatment appears to be more effective for patients with persistent symptoms of tick-borne infection. Resolution of the controversy surrounding Lyme disease should lead to improved diagnosis and treatment modelled on the approach to HIV disease.