Lyme borreliosis is the most common tick-borne, infectious disease in the northern hemisphere. Disease manifestations in the United States and Europe vary as a result of geographic distribution of different species within the genospecies Borrelia burgdorferi sensu lato, which in turn are host-specific. Certain toxigenic B. burgdorferi strains cause early disseminated disease. The ability of Borrelial organisms to break down the extracellular matrix also promotes dissemination. B. burgdorferi are eliminated by complement-mediated lysis and by T and B cell activity of the specific immune response. Yet, B. burgdorferi can evade humoral immunity by means of type of protective mechanism by which it adheres to the proteoglycan decorin in the joints and skin. A further factor in the persistence of the pathogen is altered antigen expression. Re-infection usually occurs with a different strain, although repeated infection with the same strain is also possible after a certain period of latency. New developments in serologic testing include the use of recombinant native antigen as well as antigens produced in vivo such as VlsE (variable major protein-like sequence, expressed) or decorin-binding protein A. Diagnosis continues to be complicated by seropositivity of healthy individuals, the persistence of antibodies after therapy, and a lacking humoral immune response in patients with erythema migrans.