Lyme borreliosis (LB), caused by Borrelia burgdorferi (B.b.), is the most frequently diagnosed tick-borne zoonosis in temperate zones of the Northern hemisphere. Borrelia is unique among bacteria in its ability to express a wide variety of lipoproteins on its surface, which play an essential role in pathogenesis. Surface proteins of spirochetes are important virulence determinants, immune evasion molecules and adaptation factors in the transmission and interaction with host tissues. Vast diversity in the expressed surface proteome of Borrelia in different niches and multifunctionality of proteins are the major strategies of Borrelia to avoid the destructive effect of immune system. In this review we provide deep insight into the protein:protein interactions that take place between different stages of life of Borrelia. Precise knowledge of surface proteins may help in improvement of the vaccines as well as for therapeutic agents against borreliosis.