Microorganisms have evolved elaborate strategies to adhere to host cells and to evade the host complement and immune attack, ensuring survival in various host niches and dissemination into sterile parts of the human body. Streptococcus pneumoniae (the pneumococcus) is not only a commensal of the human respiratory tract but also the etiological agent of severe and life-threatening diseases. Pneumococcal attachment to mucosal surfaces is a highly dynamic process requiring the contact of pneumococcal surface-exposed proteins with soluble or immobilized host factors. These avid interactions may trigger proteolytic cascades or result in engagement of cell surface receptors and intracellularly associated signaling machineries for subsequent uptake of pneumococci into host cells. In the present review, the intimate communication of S. pneumoniae molecules recognizing adhesive matrix molecules (microbial surface components recognizing adhesive matrix molecules) with their host counterparts and their individual role in pneumococcal colonization is discussed.