Lyme disease (LD) is the most common tick-borne disease in the United States. The overall trend has been an average annual increase in reported cases since surveillance was initiated by the Centers for Disease Control and Prevention in 1982. Ixodes ticks often carry more than one potential pathogen, and co-infection with Borrelia burgdorferi and other organisms has been reported. The impact of dual infection upon the clinical course of LD is not known. Further studies of erythema migrans-like rashes in the Southern United States have indicated that it is likely caused by a related spirochetal organism. Case reports of unusual presentations have broadened our understanding of the clinical spectrum of LD. Studies in patients with chronic Lyme arthritis have indicated that an autoimmune process may be responsible for such cases. Results of two large, placebo-controlled trials of a recombinant Lyme vaccine have been reported and results indicate that the vaccine is safe and effective in preventing LD in adults.