The overall efficacy of a recombinant vaccine for Lyme disease that is effective worldwide will depend upon the selection of one or more immunoprotective target(s) and the frequency of genetic variation, which can alter the antigenicity of the immunoprotective epitopes of the target proteins. Careful delineation of these protective epitopes on target antigens is essential for the development of vaccine candidates as well as for understanding the limitations of such vaccines. Structural models of these targets will provide critical information about conformation and specific residue surface accessibility for defining protective epitopes. Co-crystal structures with Fab fragments of protective antibodies will further delineate critical antigen surfaces. Population genetics will provide vital information on the heterogeneity of these proteins. Detailed epitope mapping will provide the information needed for the bioengineering of antigens needed to expand the specificity of a candidate vaccine.