Lyme disease is the most common vector-borne disease in the United States and Europe, caused by a tick-borne spirochete, Borrelia burgdorferi. Life cycle alternation between arthropod and mammals enhanced B. burgdorferi to adapt to two diverse niches. Although B. burgdorferi infection in these reservoir hosts appears asymptomatic, infection in human can typically cause inflammation in the skin, nervous system, musculoskeletal system and heart. In this review, we discuss the basic molecular characteristics and cell biology of B. burgdorferi and provide an overview of spirochete-induced activation of innate and adaptive immunity, resulting in particular immunopathology. Advancing understanding of the immune evasion mechanisms of B. burgdorferi provides important implications for ongoing research and clinical practice of Lyme disease.