In vitro studies and analyses of the immunodeficiency disorders that predispose to infection with Streptococcus pneumoniae indicate that efficient phagocytosis is essential for protection against this organism. Thus, antibody- and C3b-dependent opsonization and the process of ingestion, not cell-mediated immunity or post-phagocytic killing mechanisms, are stressed. It is likely that the tissue damage of pneumococcal disease also results from the interactions between antibody, complement, and phagocytic cells that permit ingestion. More effective protection against pneumococcal invasion and better management of pneumococcal disease depend on improved understanding of these interactions.