Abstract <p>Spirochetes of the genus <i>Borrelia</i> are the causative agents of vector-borne diseases, including Lyme borreliosis (LB). Clinical LB diagnosis is challenging due to the heterogeneous and nonspecific symptoms among patients further complicated by the potential for co-infection with <i>Borrelia</i> species and other pathogens. Current diagnosis is based on an indirect serological approach with limitations such as early-stage low sensitivity and cross reactivity. This review explores the potential of <i>Borrelia</i> surface proteins as biomarkers for a more accurate diagnosis of LB, with a particular interest in proteins involved in (i) tissue adhesion, essential for host colonization, (ii) antigenic variation, and (iii) immune evasion. By detailing the role of the distinct surface proteins, the review highlights their potential as biomarkers in order to improve the detection of LB, particularly in the early stages. In addition to their diagnostic value, they also represent potential targets for the development of new therapeutic strategies.</p> Keypoints <p>• <i>Various Borrelia surface proteins drive host colonization and immune evasion.</i></p> <p>• <i>Novel bacterial proteins biomarkers are needed for improved diagnosis and therapy.</i></p> <p>• <i>State of the art on Borrelia surface proteins and their associated role.</i></p> Graphical Abstract <p></p>