Streptoccus suis is a porcine commensal bacterium which can cause opportunistic infections and has zoonotic potential. We analyze the unique zoonotic clonal complex (CC) 20 in the Netherlands which diverged from non-zoonotic CC16. Gene loss, recombination and horizontal gene transfer events were the major contributors to zoonotic potential in the Netherlands. We identified four different target recognition domains (TRD’s) in a novel type I R-M system. Switching of TRD’s facilitated by the integrase gene was postulated. The streptococcal adhesion protein was demonstrated to interact with human and porcine intestinal cell-lines. Translocation across the human intestinal epithelium was established, supporting the hypothesis that S. suis infections can occur through the gastrointestinal tract. The first reinfection with S. suis in a patient was studied using the whole genome sequences of the first and second isolated bacteria. The bacterial strains were highly similar but unrelated because the estimated substitution rate would be too high. A serological array with bacterial polysaccharides was calibrated using rabbit sera and unexposed child sera. It was validated using sera from unexposed, exposed and infected adults from Vietnam. We showed low sensitivity, but using polysaccharides as antigens could be promising. Serotype 9 was further investigated using whole genome comparison with both invasive and carriage isolates from pigs. A wide diversity among carriage strains was found. Whereas, virulent isolates belonged to a single clonal expansion. This thesis broadened the knowledge of the Dutch S. suis population, in particular CC20, and identified factors that are important for virulence and zoonotic potential.