Lyme disease is a common tick-borne illness typically caused by the spirochete Borrelia burgdorferi, which is transmitted to humans via the deer tick (Genus Ixodes). In pediatrics, Lyme disease most commonly affects those age 5–15 years living in the northeastern or midwestern United States. Initially, the infection causes rash, but in days to weeks can progress to affect the central/peripheral nervous system and the heart. Late in the infection, within months, joints are affected. Lyme disease can be treated successfully with antibiotics, so it is important to recognize the signs and symptoms. This chapter describes the clinical manifestations, the diagnosis, and treatment of Lyme disease at each stage.