Research of recent years on Lyme disease has greatly increased our understanding on antigenic structures and genotypic variability of the aetiological agent, Borrelia (B.) burgdorferi sensu lato, as well as on mechanisms underlying host-parasite interactions and induction/mode of action of protective immune responses. A vaccine formula on the basis of the outer surface lipoprotein A (OspA), previously developed in our laboratory, has successfully been tested in a clinical trial involving nearly 10,000 subjects in the USA. The OspA vaccine is unique in that it protects the mammalian host from infection by eliminating spirochaetes from the vector, but does not cure an established disease. This is because spirochaetes express OspA exclusively in the tick, but not when transmitted into the vertebrate host. For Europe, a more complex vaccine formula is required in order to achieve full protection. This is due to the higher degree of heterogeneity of OspA molecules among isolates of B. burgdorferi in Europe and the inability of the monovalent vaccine to convey complete cross-protection.