Streptococcus suis is known as a pathogenic organism that causes respiratory disease and central nervous system disease in pigs, as well as meningitis in humans; however, it also lives without causing disease as a carriage species in pig tonsils. We used a bioinformatics approach to examine the genomes of 1,018 S. suis strains, which consisted of both clinical and non-clinical strains. Both types of strains are spread throughout the core genome phylogeny, which suggests that the evolution to cause clinical disease has occurred multiple times. We examined whether 24 independent instances of transitions to clinical disease were repeatedly accompanied by the acquisition of virulence genes, as well as examining related shifts in genome size and gene number. We found the transition to clinical disease agent is correlated with the amount of repetitive DNA, as well as with a loss of phage-related genes. As extensive changes to gene content and gene number implicate horizontal gene transfer, we examined gene phylogenies for each of over a thousand core genes to reveal the pattern of gene exchange within this species. Our genomics approach provides insight into the divide between carriage and clinical isolates in S. suis; these patterns of genomic changes may help us understand a generalised evolutionary path to pathogenicity.