The pathogenesis of pneumococcal infection is a complex interplay between pneumococcal virulence determinants and the host immune response. Molecular studies have considerably advanced our knowledge and understanding of the precise structures and functions of the different determinants and their pathogenic roles. This review describes the mechanisms by which pneumococci attach, invade, evade lung defences and cause severe disease. Better understanding of the critical steps in this complex process will enable more effective clinical intervention to be developed to reduce the mortality exacted by this versatile pathogen.