Streptococcus suis is an opportunistic bacterial pathogen in pigs, that can cause zoonotic infections in humans resulting in meningitis, streptococcal toxic-shock like syndrome or septicaemia. When we understand what enables S. suis to cause zoonotic infections, we can design strategies to prevent these infections. In this thesis, I used different approaches to better understand which traits contribute to the zoonotic potential of S. suis. We performed a systematic review and a molecular epidemiology study in which we identified 236 cases of zoonotic S. suis infection in Europe and identified zoonotic lineages not yet described in Europe. In a systematic review, we evaluated the contribution to zoonotic potential of 124 virulence factors. In a subsequent genomic meta-analysis, we found that 53 of these factors are core genes and thus less likely to contribute virulence. Phase variation is a bacterial mechanism that allows for rapid phenotypic adaptation, thereby potentially contributing to virulence. Phase variable restriction modification system allow for phase variation. A zoonotic S. suis lineage has acquired such a phase variable restriction modification system. We characterized the system and show its phase-variability and its phase-dependent genome methylation, gene expression and contribution to virulence. S. suis infections can be foodborne, so we developed an intestinal organoid model to study its foodborne pathogenesis. In the intestinal organoids, we found a link between genotype and translocation across the human epithelial barrier. We show that the translocation of zoonotic S. suis was dependent on the presence of Gb3-positive cells, a cell population targeted by other enteric pathogens as well.