Lyme disease is the most common tick-borne disease in the United States. This review details the risk factors, clinical presentation, treatment, and prophylaxis for the disease. Information was obtained from a search of the PubMed and MEDLINE databases (keyword: Lyme disease) for articles published from August 31, 1997, through September 1, 2007. Approximately 20,000 cases of Lyme disease are reported annually. Residents of the coastal Northeast, northwest California, and the Great Lakes region are at highest risk. Children and those spending extended time outdoors in wooded areas are also at increased risk. The disease is transmitted to humans through the bite of the Ixodes tick (Ixodes scapularis and Ixodes pacificus). Typically, the tick must feed for at least 36 hours for transmission of the causative bacterium, Borrelia burgdorferi, to occur. Each of the 3 stages of the disease is associated with specific clinical features: early localized infection, with erythema migrans, fever, malaise, fatigue, headache, myalgias, and arthralgias; early disseminated infection (occurring days to weeks later), with neurologic, musculoskeletal, or cardiovascular symptoms and multiple erythema migrans lesions; and late disseminated infection, with intermittent swelling and pain of 1 or more joints (especially knees). Neurologic manifestations (neuropathy or encephalopathy) may occur. Diagnosis is usually made clinically. Treatment is accomplished with doxycycline or amoxicillin; cefuroxime axetil or erythromycin can be used as an alternative. Late or severe disease requires intravenous ceftriaxone or penicillin G. Single-dose doxycycline (200 mg orally) can be used as prophylaxis in selected patients. Preventive measures should be emphasized to patients to help reduce risk.