Streptococcus pneumoniae probably possesses a redundant set of factors required for colonization of the nasopharynx and invasive disease, because of its strict relationship with its human host and relatively small genome size (approximately 2.1 Mb). Nevertheless, transcriptional regulation of genes encoding factors required for in vivo growth is predicted to be important on two fronts: in the transition from carriage to invasive disease and within different microniches of the nasopharynx. The importance of both serotype-specific and host tissue-specific virulence factors during infection and disease has been highlighted by the recent identification of novel virulence factors in this organism coupled with the release of complete genome sequences from two strains. These studies add to the foundation of knowledge of classical S. pneumoniae virulence factors such as polysaccharide capsule and pneumolysin, which have well-documented roles in pathogenesis.