Streptococcus pneumoniae is a complex human pathogen and a major cause of morbidity and mortality. The genetic background of pneumococci and the chemical structure of their capsules is largely unraveled as well as the basic role of anticapsular antibodies and other opsonins interacting to enhance phagocytosis. Many experimental studies are improving our knowledge on the complex molecular mechanisms underlying those events. Pneumococcal optimal clearance requires the cooperation of a plethora of reactions from both innate and adaptive immunity. The last advances in the complexity of the immune response and protection are reviewed: phagocyte-pneumococcus interactions mediated by opsonins; the role of complement, reactive C protein and natural antibodies; details of novel immune evasion mechanisms; the complex role of the inflammatory mediators in the susceptibility to pneumococcal infections; why capsular polysaccharides do not yield an anamnestic response after primary immunization; the central question of whether T cells regulate in-vivo anti-polysaccharide immunoglobulin responses to intact pathogens. All of these are topics where new data and some answers are offered. The state of the art on the research of pneumococcal protein vaccines as an alternative to plain polysaccharide or conjugated vaccine and the establishment of immunologic correlates of protection to facilitate efficacy trial assessment are also reviewed.