Surface-exposed proteins of pathogenic bacteria are considered as potential virulence factors through their direct contribution to host-pathogen interactions. The specific interaction of bacterial proteins with host proteins often subverts the physiologic function of host-derived proteins, and therefore the bacterial proteins are considered as key players in the infectious process. The direct binding of host proteins is exploited by the pathogens for colonization, host tissue invasion, or immune evasion. Strikingly, surface proteins such as ABC transporters are also implicated in bacterial pathogenesis through their role in maintenance of bacterial fitness. Here, we are interested in surface-exposed proteins of Streptococcus pneumoniae, which interact with host proteins including proteins of the extracellular matrix, serum proteins, or ectodomains of cellular host receptors. These bacterial proteins are termed collectively adhesins or MSCRAMMs (microbial surface components recognizing adhesive matrix molecules). We have shown that choline-binding proteins and proteins that lack classic features of surface proteins such as a signal peptide that is required for protein secretion or a membrane anchor motif represent a major class of adhesins produced by S. pneumoniae.